SK85693A3 - 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6- -deoxytetracyclines - Google Patents

Abstract

Disclosed are compounds of general formulas (I) and (II) wherein R, R3, R4 and W are defined in the specification. Considering the effectivity of the compounds of general formula (I) and (II) as antibiotics they are used as prevention, treatment or fighting bacterial contaminations of warm-blooded animals. Disclosed is also method for their preparation by reaction of compounds of general formula (III) with nucleofile compound od general formula (HW), with general symbols of the meaning defined in specification. Disclosed are also compounds of general formula (III) as intermediates for production of compounds of formulas (I) and (II) and pharmaceutical and veterinary preparations based on compounds of formulas (I) and (II).

Description

7- (substituted) -9 - [(substituted glycyl) amido] -6-dimethyl-6-deoxytetracyclines and process for their preparation

Technical field

The invention relates to novel [4S- (4alpha, 12aalpha)] - 4 (dimethylamino) -7- (substituted) -9- [(substituted glycyl) amido] -1,4,4a, 5,5a, 6,11,12a -octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamides, hereinafter referred to as 7- (substituted) -9 - [(substituted glycyl) amido] -6-demethyl1-6 -deoxytetracyklíny. These compounds exhibit antibiotic activity against a wide variety of organisms, including organisms that are resistant to tetracyclines. For this reason, they are useful as antibiotics.

The invention also relates to novel 9 - [(haloacyl) amido] 7- (substituted) -6-demethyl-6-deoxytetracyclines which are useful intermediates for the production of the novel compounds of the invention. The invention also relates to novel processes for the preparation of novel compounds and intermediates.

SUMMARY OF THE INVENTION

The present invention provides novel 7- (substituted) -

9 - [(substituted glycyl) amido] -6-demethyl-6-deoxytetracyclines of formulas I and II, which exhibit antibacterial activity. The invention also relates to the treatment of infectious diseases of warm-blooded animals using these novel compounds, to pharmaceutical compositions based on these compounds, to novel intermediates for the production of terminal compounds according to the invention, and to methods of making all of these compounds. In particular, the present invention provides compounds of formulas I and II which exhibit enhanced antibiotic activity against tetracycline resistant strains and which exhibit high activity against tetracycline sensitive strains.

Accordingly, in a first aspect, the present invention provides compounds of formula I or II

where

R is halogen selected from bromine, chlorine, fluorine and iodine; or a group of the formula -NR 1 R ² , wherein when R is a group of the formula -NR 1 R ² are arl; represents a hydrogen atom,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-met.ylpropyl

1,1-dimethylethyl;

when R ¹ represents methyl or ethyl,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

when R ¹ represents n-propyl,

R ² is n-propyl, 1-methylethyl, n-butyl,

1-methylpropyl or 2-methylpropyl;

when R ¹ represents 1-methylethyl

R ² = n-butyl, 1-methylpropyl, or

2-methylpropyl;

when R ¹ represents n-butyl

R ² is n-'butyl, 1-methylpropyl, or

2-methylpropyl;

and when R ¹ represents 1-methylpropyl,

R ² represents 2-methylpropyl; R ³ represents a hydrogen atom; straight or branched (C 4 -C 8) alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-mercaptoalkyl having 1 to 4 carbon atoms selected from mercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl and α-mercaptopropyl; α-hydroxy (C až-Calkyl) alkyl group selected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl and α-hydroxypropyl; carboxyalkyl of 1 to 8 carbon atoms in the alkyl radical; (C až-C 10ry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; substituted (C 6 -C 10) aryl group [in which the substituents are selected from hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 3) trihaloalkyl, nitro, amino, cyano, (C 1 -C 4) alkoxycarbonyl in alkoxy radical, (C 1 -C 3) alkylamino and carboxy]; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; substituted (C7 -C9) aralkyl group [in which the substituents are selected from the group consisting of halogen, (C1 -C4) alkyl, nitro, hydroxy, amino, (C1 -C4) mono- or dialkylamino in each of the aryl radicals, alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, cyano and carboxy]; R ⁴ is hydrogen or (C1-C6) -alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl,

pentyl and hexyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

W is hydroxyamino; (C roz-C 12) monoalkylamino group having a straight or branched alkyl chain selected from heptyl, btyl, nonyl, decyl, undecyl, dodecyl and diastereomers and enantiomers of these branched monoalkylamino groups; straight or branched (C 1 -C 4) fluoroalkylamino group selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3,3,2,2-pentafluoropropyl, 2,2-difluoropropyl, 4,4,4-trifluorobutyl and 3,3-difluorobutyl; (C až-C 8) monocycloalkylamino group selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] hept-2- yl, bicyclo [2.2.2] oct-2-yl and diastereomers and enantiomers of these C 3 -C 8 monocycloalkylamino groups; C 4 -C 10 mono [(cycloalkyl) alkyl] amino in a cycloalkyl radical with a (cycloalkyl) alkyl chain selected from (cyclopropyl) methyl, (cyclopropyl) ethyl, (cyclobutyl) methyl, (trans 2-methylcyclopropyl) methyl and ( cis-2-methyl-cyclobutyl) methyl; (C 3 -C 10) monoalkenyl and monoalkynylamino having an alkenyl or alkynyl radical selected from the group consisting of allyl, 3-butenyl, 2-butenyl (cis or trans), 2-pentenyl, propynyl, 4-octenyl,

2,3-dimethyl-2-butenyl, 3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl; (C6 -C10) monoarylamino having an aryl radical selected from phenyl and naphthyl; (C až-C 10) aralkylamino group selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2- (naphthyl) methyl, 1- (naphthyl) methyl and phenylpropyl; (C až-C) monoarylamino group whose aryl radical is substituted with substituents selected from Cyl-C ac acyl, C až-C ac acylamino, C až-C alkyl alkyl, Co-C mon monoalkylamino or Cky-C dial dial dialkylamino C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl, amino, carboxy, cyano, halogen, hydroxy, nitro and C 1 -C 3 trihaloalkyl 3 carbon atoms; straight or branched symmetrical C 6 -C 14 alkyl radical selected from dibutyl, diisobutyldisacutyl, dipentyl, diisopentyl, disac. pentyl-, dihexyl-, diisohexyl- and disa-hexylamino; symmetrical dicycloalkylamino of 6 to 14 carbon atoms selected from dicyclopropyl, dicyclobutyl, dicyclopentyl, di (cyclopropyl) methyl, dicyclohexyl and dicycloheptylamino; straight or branched unsymmetrical (Clam-C dial) straight-chain or branched alkyl radicals, wherein the total number of carbon atoms in the two substituents is not more than 14; unsymmetrical dicycloalkylamino having 4 to 14 carbon-cycloalkyl radicals, wherein the total number of carbon atoms in the two substituents is not more than 14; C 2 -C 8 azacycloalkyl and substituted C 2 -C 8 azacycloalkyl selected from the group consisting of 4-methylpiperidine, 4-hydroxypiperidine,

4- (hydroxymethyl) piperidine and 4- (aminomethyl) piperidine, cis-3,4-dimethylpyrrolidinyl, trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo [2.1.1] hex-2-yl,

5-azabicyclo [2.1.1] hex-5-yl, 2-azabicyclo [2.2.1] hept-2-yl, 7-azabicyclo [2.1] hept-7-yl, and 2-azabicyclo [2.2.2] oct- 2-yl and diastereomers and enantiomers of these C 2 -C 8 azacycloalkyl and substituted azacycloalkyl groups; a substituted 1-azaoxacycloalkyl group selected from 2-alkylmorpholinyl having 1 to 3 carbon atoms in the alkyl moiety, 3-alkylisoxazolidinyl having 1 to 3 carbon atoms in the alkyl moiety, tetrahydrooxazinyl and 3,4-dihydrooxazinyl;

[1, n] -diazacycloalkyl and a substituted [1, n] diazacycloalkyl group selected from piperazinyl, 2-alkylpiperazinyl having 1 to 3 carbon atoms in the alkyl moiety, 4-alkylpiperazinyl having 1 to 3 carbon atoms in the alkyl moiety,

2,4-dimethylpiperazinyl, 4-alkoxypiperazinyl having 1 to 4 carbon atoms in the alkoxy moiety, 4-aryloxypiperazinyl having 6 to 10 carbon atoms in the aryl moiety, 4-hydroxypiperazinyl, 2,5-diazabicyclo [2.2.1] hept-2- yl, 2,5-diaza-5-methylbicyclo [2.2.1] hept-2-yl, 2,3-diaza-3-methylbicyclo [2.2.2] oct-2-yl, 2,5-diaza -5,7-dimethylbicyclo- [2.2.2] oct-2-yl and diastereomers or enantiomers of this [1, n] -diazacycloalkyl and substituted [1, n] -diazacycloalkyl; a 1-azathiacycloalkyl group and a substituted 1-azathiacycloalkyl group selected from the group consisting of thiomorpholinyl, 2-alkylthiomorpholinyl having 1 to 3 carbon atoms in the alkyl moiety and 3-cycloalkylthiomorpholinyl having 3 to 6 carbon atoms in the cycloalkyl moiety; N-azolyl and substituted N-azolyl selected from 1-imidazolyl, 2-alkyl-1-imidazolyl of 1 to 3 carbon atoms in the alkyl moiety, 3-alkyl-1-imidazolyl of 1 to 3 carbon atoms in the alkyl moiety, 1-pyrrolyl, 2alkyl-1-pyrrolyl of 1 to 3 carbon atoms in the alkyl moiety, 3-alkyl-1-pyrrolyl of 1 to 3 carbon atoms in the alkyl moiety, 1-pyrazolyl, 3-alkyl-1-pyrazolyl of 1 to 3 carbon atoms in the alkyl moiety, indolyl,

1- (1,2,3-triazolyl), 4-alkyl-1- (1,2,3-triazolyl) with 1 to 3 carbon atoms in the alkyl moiety, 5-alkyl-1- (1,2,3-triazolyl) ) having 1 to 3 carbon atoms in the alkyl moiety, 4- (1,2,4-triazolyl), 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl; (heterocyclyl) amino wherein the heterocyclic radical is selected from 2- or 3-furanyl, 2- or 3-thienyl,

2-, 3- or 4-pyridyl, 2- or 5-pyridazinyl, 2-pyrazinyl, 2-imidazolyl, benzimidazolyl and benzothiazolyl and substituted (heterocyclyl) amino-. _r , a group (wherein the substituents are selected from straight or branched (C 1 -C 6) alkyl; (heterocyclyl) methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3 or 3); 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino, (benzimidazolyl) methylamino and (benzothiazolyl) methylamino and substituted (heterocyclyl) methylamino (wherein the substituents are selected from straight and branched (C 1 -C 6) alkyl; carboxyalkylamino) 4 carbon atoms in the alkyl moiety selected from aminoacetic acid, α-aminopropionic acid, β-aminopropionic acid, α-aminobutyric acid, β-aminobutyric acid, and enantiomers of these carboxyalkylamino groups having 2 to 4 carbon atoms in the alkyl moiety; 1,1-disubstituted a hydrazino group selected from 1,1-dimethylhydrazino, N-aminopiperidinyl, C 1 -C 4 alkoxyamino (wherein the alkoxy substituents are selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethylethoxy; 1-diethylhydrazino and N-aminopyrrolidinyl; (C až-C 8) cycloalkoxyamino group selected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy, cis-

1,2-dimethylcyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, bicyclo [2.2.1] hept-2-yloxy, bicyclo [2.2.2] oct-2-yloxy and diastereomers and enantiomers of these 3-8 cycloalkoxyamino groups carbon atoms; (C 6 -C 10) aryloxyamino selected from phenoxyamino, 1, naphthyloxyamino and 2-naphthyloxyamino; (C 7 -C 11) arylalkoxyamino group selected from benzyloxyamino, 2-phenylethoxyamino,

1-phenylethoxyamino, 2- (naphthyl) methoxyamino, 1- (naphthyl) methoxyamino and phenylpropoxyamino; [beta- or gamma-acylamido] C1-C3 alkylamino group selected from the group consisting of

2- (formamido) ethylamino, 2- (acetamido) ethylamino, 2- (propionylamido) ethylamino, 2- (acetamido) propylamino, 2- (formamido) propylamino, and enantiomers of these [beta- or gamma-acylamido] alkylamino groups having 1 up to 3 carbon atoms in the acyl radical; β- or gamma-alkoxyalkylamino having 1 to 3 carbon atoms in the alkoxy moiety selected from the group consisting of 2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino, 2-methoxypropylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 3,3-diethoxypropylamino and the enantiomers of these β- or gammaalkoxyalkylamino groups having 1 to 3 carbon atoms in the alkoxy radical; C 2 -C 4 β-, gamma- or 8-hydroxyalkylamino group selected from 2-hydroxyethylamino, 2-hydroxypropylamino, 3-hydroxypropylamino and 4-hydroxybutylamino; or

R ³ and W together represent a radical of the formula - (CH 2) n (R ⁵ ) N- wherein n is a number of 3 to 4 and the radical of the formula -CH 2 CH (OH) CH ₂ (R ⁵ ) N- wherein R ⁵ represents a hydrogen atom or (C 1 -C 3) acyl group selected from formyl, acetyl and propionyl, haloacyl group of 2 to 3 carbon atoms selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl;

R ⁶ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered heterocyclic radicals having an aromatic or saturated ring containing 1 heteroatom of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein Z represents a nitrogen, oxygen, sulfur or selenium atom such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered aromatic ring heterocyclic radicals containing two heteroatoms of nitrogen, oxygen, sulfur or selenium, to which is optionally fused a benzo or pyrido group of the general formula

wherein each of Z and Z ¹ represents a nitrogen, oxygen, sulfur or selenium atom such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5] -b] pyridyl or pyridylimidazolyl, a five-membered saturated ring heterocyclic radical containing one or two nitrogen, oxygen, sulfur or selenium heteroatoms to which an oxygen heteroatom is attached

[wherein A represents a hydrogen atom; straight or branched (C 1 -C 4) alkyl; (C 6-Cry) aryl; substituted (C 6-Cry a) aryl group (wherein the substituents are selected from the group consisting of halogen, (C až-C alko) alkoxy, (C až-Ckyl) trihaloalkyl, nitro, amino, (C alko-C ažony) alkoxycarbonyl, (Clam-C alky alky) alkoxy) having 1 to 3 carbon atoms and carboxy); (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl] such as gamma-butyrolactam, gamma-butyrolactone, imidazolidinone or N-aminoimidazolidinone, 6-membered heterocyclic radicals containing 1 to 3 aromatic ring atoms nitrogen, such as pyridyl, pyridazinyl, pyrazinyl, symtriazinyl, unsymmetriazinyl, pyrimidinyl or alkylthiopyridazinyl having 1 to 3 carbon atoms in the alkyl moiety and six-membered saturated ring heterocyclic radicals containing one or two nitrogen, oxygen, sulfur or selenium to which an oxygen heteroatom such as 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl -2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or 2-dioxothiomorpholinyl; - (CH ₂ ) _n COOR ⁸ wherein ⁿ is 0-4 and R ⁸ is selected from hydrogen; straight or branched (C až-C alkyl) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

R ⁷ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C7 -C9) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered heterocyclic radicals having an aromatic or saturated ring containing 1 heteroatom of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein Z represents a nitrogen, oxygen, sulfur or selenium atom such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered heterocyclic aromatic ring radicals containing two heteroatoms of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein each of Z and Z ¹ represents a nitrogen, oxygen, sulfur or selenium atom such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5-b] pyridyl or pyridylimidazolyl, a five-membered saturated ring heterocyclic radical containing one or two heteroatoms of nitrogen, oxygen, sulfur or selenium to which an oxygen heteroatom is attached

[wherein A represents a hydrogen atom; straight or branched (C 1 -C 4) alkyl; (C 6-Cry) aryl; substituted (C 6-Cryry) aryl group (wherein the substituents are selected from the group consisting of halogen, (C 4-C alko) alkoxy, (C až-C tr) trihaloalkyl, nitro, amino, cyano, (C alko-C alko) alkoxycarbonyl, (C alko-C časti) alkoxy) (C 1 -C 3 alkylamino and carboxy); (C až-C 9) aralkyl group selected from

- a group comprising benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl], such as gamma-butyrolactam, gamma-butyrolactone, imidazolidinone or N-aminoimidazolidinone, six-membered aromatic ring heterocyclic radicals containing 1 to 3 nitrogen heteroatoms, such as pyridinyl, pyridinyl, , pyrazinyl, sym-triazinyl, unsymmetriazinyl, pyrimidinyl or alkylthiopyridazinyl having 1 to 3 carbon atoms in the alkyl moiety and six-membered saturated ring heterocyclic radicals containing one or two heteroatoms of nitrogen, oxygen, sulfur or selenium to which an oxygen heteroatom is attached, such as 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or 2-dioxothiomorpholinyl; - (CH ₂ ) _n COOR ⁸ wherein n is 0-4 and R ⁸ is selected from hydrogen; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

wherein both R ⁸ and R ⁷ do not simultaneously represent hydrogen; or

R ⁶ and R ⁷ taken together are - (CH2) 2 B (CH2) 2-, wherein ^{B re} dstavuje (CH2) _n and n = 0-1, -NH, -N-alkyl [ wherein the alkyl is straight or branched and contains 1 to 3 carbon atoms], -N-alkoxy of 1 to 4 carbon atoms, an oxygen atom, a sulfur atom, or substituted analogues thereof selected from the group consisting of proline (L or D), ethyl ( L or D) prolinate, morpholine, pyrrolidine or piperidine;

and pharmacologically acceptable salts thereof with organic or inorganic acids or metal complexes.

Preferred compounds of the invention are those compounds of formula I or II wherein

R is halogen selected from bromine, chlorine, fluorine and iodine; or --NR @ 1 --R @ ² wherein R @ ¹ is --NR @ 1 R @ ² and R ^{@ 1} is hydrogen,

R ² is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;

and when R ¹ represents methyl or ethyl,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

jv

R ³ represents a hydrogen atom; straight or branched (C 4 -C 8) alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-hydroxy (C 1 -C 4) alkyl group selected from hydroxymethyl, α-hydroxyethyl, ahydroxy-1-methylethyl and α-hydroxypropyl; carboxyalkyl of 1 to 8 carbon atoms in the alkyl radical; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; substituted (C 6 -C 10) aryl group [in which the substituents are selected from hydroxy, halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl and carboxy]; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; substituted C 7 -C 9 aralkyl [wherein the substituents are selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, cyano and carboxy];

R ⁴ is hydrogen or C 1 -C 4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

W is hydroxyamino; a C7 -C12 monoalkylamino group selected from the group consisting of heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and diastereomers and enantiomers of these branched monoalkylamino groups; (C až-C) monocycloalkylamino group selected from the group consisting of cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and diastereomers and enantiomers of these 8-monocycloalkyloamino groups alkyl; straight or branched (C 1 -C 4) fluoroalkylamino group selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2,2-difluoropropyl and

3,3-difluorobutyl; C 4 -C 10 mono [(cycloalkyl) alkyl] amino in a cycloalkyl radical having a (cycloalkyl) alkyl chain selected from (cyclopropyl) methyl, (cyclopropyl) ethyl, (cyclobutyl) methyl, (trans-

2-methylcyclopropyljmethyl and (cis-2-methylcyclobutyl) methyl; a (C 3 -C 10) monoalkenyl and monoalkynylamino group in an alkenyl or alkynyl radical having an alkenyl or alkynyl chain selected from the group consisting of allyl,

3-butenyl, 2-butenyl (cis or trans), 2-pentenyl, propynyl, 4-octenyl, 2,3-dimethyl-2-butenyl and 3-methyl-2-butenyl; (C6 -C10) monoarylamino having an aryl radical selected from phenyl and naphthyl; (C až-C 10) aralkylamino group selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2- (naphthyl) methyl, 1- (naphthyl) methyl and phenylpropyl; straight or branched symmetrical C 6 -C 14 alkyl radical selected from dibutyl-, diisobutyl-, disac-butyl-, dipentyl-, diisopentyl- and disacentyl-; symmetrical dicycloalkylamino of 6 to 14 carbon atoms selected from dicyclopropyl, dicyclobutyl, dicyclopentyl and di (cyclopropyl) methylamino; straight or branched unsymmetrical dialkylamino of 3 to 14 carbon atoms, the total number of carbon atoms in both substituents not exceeding 14; unsymmetrical dicycloalkylamino of 4 to 14 carbon atoms wherein the total number of carbon atoms in the two substituents is not more than 14; C 2 -C 8 azacycloalkyl and substituted C 2 -C 8 substituted azacycloalkyl selected from the group consisting of 4-methylpiperidine, 4-hydroxypiperidine, 4- (hydroxymethyl) piperidine and 4- (aminomethyl) piperidine, cis-3,4-dimethylpyrrolidinyl trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo [2.2.1] hept-2-yl, 7-azabicyclo [2.2.1] hept-7-yl, and 2-azabicyclo [2.2.2] oct-2- yl and diastereomers and enantiomers of these C 2 -C 2 azacycloalkyl and substituted azacycloalkyl groups; substituted 1-azaoxacycloalkyl group selected from 2-alkylmorpholinyl having 1 to 3 carbon atoms in the alkyl moiety, 3-alkylisoxazolidinyl having 1 to 3 carbon atoms in the alkyl moiety, and tetrahydrooxazinyl;

[1, n] -diazacycloalkyl and a substituted [1, n] -diazacycloalkyl group selected from piperazinyl, 2-alkylpiperazinyl having 1 to 3 carbon atoms in the alkyl moiety, 4-alkylpiperazinyl having 1 to 3 carbon atoms in the alkyl moiety, 2,4-dimethylpiperazinyl, 4-alkoxypipera: 1 to 4 carbon atoms in the alkoxy moiety, 4-aryloxypiperazinyl with 6 to 10 carbon atoms in the aryl moiety, 4-hydroxypiperazinyl, 2,3-diaza-3-methylbicyclo [2.2.2] oct-2-yl, 2,5-diaza-5,7-dimethylbicyclo [2.2.2] oct-2-yl, and diastereomers or enantiomers of this [1, n] -diazacycloalkyl and substituted [1, n] -diazacycloalkyl; 1-azathiacyclo-20 alkyl and substituted 1-azathiacycloalkyl selected from thiomorpholinyl, 2-alkylthiomorpholinyl having 1 to 3 carbon atoms in the alkyl moiety and 3-cycloalkylthiomorpholinyl having 3 to 6 carbon atoms in the cycloalkyl moiety; N-azolyl and substituted N-azolyl selected from 1-imidazolyl, 1-pyrrolyl, 1-pyrazolyl, 3-alkylpyrazolyl of 1 to 3 carbon atoms in the alkyl moiety, indolyl, 1- (1,2,3-triazolyl) 4- (1,2,4-triazolyl),

1-tetrazolyl, 2-tetrazolyl and benzimidazolyl; a (heterocyclyl) methylamino group selected from 2- or 3-furylmethylamino,

2- or 3-thienylmethylamino, 2-, 3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino, 2-pyrazinylmethylamino, 2- (imidazolyl) methylamino, (benzimidazolyl) methylamino and (benzothiazolyl) methylamino and substituted (heterocyclyl) methylamino (wherein the substituents are selected from straight or branched (C 1 -C 6) alkyl; (C 2 -C 4) carboxyalkylamino group selected from aminoacetic acid, α-aminopropionic acid, β-aminopropionic acid, α-aminobutyric acid acid, β-aminobutyric acid and the _{enantiomers:?} carboxy 2 -C 4 alkyl, 1,1-hydrazino disubštituoyanú selected from 1,1dimetylhydrazino, N-aminopiperidinyl and 1,1-dietylhydrazinof alkoxyamino of 1 to 4 carbon carbon (wherein the alkoxy substituents are selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy C3-C8 cycloalkoxyamino selected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy, cis-1,2-dimethylcyclopropoxy and cyclobutoxy and diastereomers and enantiomers of these cycloalkoxyamino groups 8 carbon atoms; (C 6 -C 10) aryloxyamino selected from phenoxyamino, 1-naphthyloxyamino and 2-: naphthyloxyamino; (C až-C 11) arylalkoxyamino group selected from benzyloxyamino;

2-phenylethoxyamino, 1-phenylethoxyamino, 2- (naphthyl) methoxyamino, 1- (naphthyl) methoxyamino and phenylpropoxyamino; [beta] - or gamma-acylamido] C1-C3 alkylamino group selected from 2- (formamido) ethylamino, 2- (acetamido) ethylamino, 2- (propionylamido) ethylamino, 2- (acetamido) propylamino, 2- (formamido) propylamino and enantiomers of these [beta- or gamma-acylamido] alkylamino groups having 1 to 3 carbon atoms in the acyl residue; β- or gamma-alkoxyalkylamino having 1 to 3 carbon atoms in the alkoxy moiety selected from 2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino, 2-methoxypropylamino, 3-methoxypropylamino,

3-ethoxypropylamino, 3,3-diethoxypropylamino and enantiomers of these .beta.- or .gamma.-alkoxyalkylamino groups having 1 to 3 carbon atoms in the alkoxy radical; (C 2 -C 4) β-, gamma- or δ-hydroxyalkylamino group selected from 2-hydroxyethylamino, 3-hydroxypropylamino and 4-hydroxybutylamino; or

R ³ and W together represent a radical of the formula - (CH 2) n (R ⁵ ) N- wherein n is a number of 3 to 4 and the radical of the formula -CH 2 CH (OH) CH ₂ (R ⁵ ) N- wherein R ⁵ represents a hydrogen atom or (C 1 -C 3) acyl group selected from formyl, acetyl and propionyl, haloacyl group of 2 to 3 carbon atoms selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl;

R ⁶ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered heterocyclic radicals having an aromatic or saturated ring containing 1 heteroatom of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein Z represents a nitrogen, oxygen, sulfur or selenium atom such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuran, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered aromatic ring heterocyclic radicals containing two heteroatoms of nitrogen, oxygen, sulfur or selenium to which is optionally fused a benzo group or a pyrido group of the general formula

wherein each of Z and Z ¹ represents a nitrogen, oxygen, sulfur or selenium atom such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5-b] pyridyl or pyridylimidazolyl, five-membered saturated ring heterocyclic radicals containing one or two nitrogen, oxygen, sulfur or selenium heteroatoms to which an oxygen heteroatom is attached

[wherein A represents a hydrogen atom; straight or branched (C1-C6) alkyl; 4 carbon atoms; (C 6-Cry) aryl; aralkyl of 7 to 9 carbon atoms selected from _<t, benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl], such as .gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or N-aminoimidazolidinone; - (CH ₂ ) 4 COOR ⁸ wherein n is 0 to 4 and R ⁸ is selected from hydrogen; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

R ⁷ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered heterocyclic radicals having an aromatic or saturated ring containing 1 heteroatom of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein Z represents a nitrogen, oxygen, sulfur or selenium atom such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenol azolyl; aromatic ring heterocyclic radicals containing two heteroatoms of nitrogen, oxygen, sulfur or selenium to which is optionally fused a benzo or pyrido group of the general formula

wherein each of Z and Z ¹ represents a nitrogen, oxygen, sulfur or selenium atom such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5-b] pyridyl or pyridylimidazolyl, a five-membered saturated ring heterocyclic radical containing one or two heteroatoms of nitrogen, oxygen, sulfur or selenium to which an oxygen heteroatom is attached

A [wherein A represents a hydrogen atom; straight or branched (C 1 -C 4) alkyl; (C 6-Cry) aryl; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl; and phenylpropyl] such as gamma-butyrolactam, gamma-butyrolactone, imidazolidinone or N-aminoimidazolidinone residues; - (CH 2) _n COOR ⁸ wherein n is 0 to 4 and R ⁸ is selected from hydrogen; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

wherein both R ⁶ and R ⁷ do not simultaneously represent hydrogen atoms; or

R ⁶ and R ⁷ taken together are - (CH 2) 2 ^{p (CH} 2) 2 '' ^{wherein B} is (CH 2) _n and n = 0-1, -NH, -N-alkyl [ in which the alkyl is straight or branched and contains 1 to 3 carbon atoms], -N-alkoxy of 1 to 4 carbon atoms, an oxygen atom, a sulfur atom or substituted analogues thereof selected from the group consisting of (L or Q) proline, ethyl ( L or D) prolinate, morpholine, pyrrolidine or piperidine;

and pharmacologically acceptable salts thereof with organic or inorganic acids or metal complexes.

Particularly preferred compounds of the invention are those compounds of formula I or II wherein

R is halogen selected from bromine, chlorine, fluorine and iodine; or a group of the formula -NR 1 -R ² _{,; ?} wherein when R is -NR 1 R ² and R ¹ is hydrogen,

R ² is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;

and when R ¹ represents methyl or ethyl,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

R ³ represents a hydrogen atom; straight or branched (C 4 -C 6) alkyl group selected from butyl, isobutyl, pentyl and hexyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

(C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl;

R ⁴ is hydrogen or C 1 -C 3 alkyl selected from methyl, ethyl, propyl and isopropyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

W represents a C 7 -C 6 monoalkylamino group selected from the group consisting of heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the diastereomers and enantiomers of these branched monoalkylamino groups, straight or branched C 1-4 fluoroalkylamino; 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 2,2-difluoropropyl; (C až-C) monocycloalkylamino group selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and diastereomers and enantiomers of these (C 3-C mon) monocycloalkylamino groups; a mono [(cycloalkyl) alkyl] amino group having 4 to 10 carbon atoms in a cycloalkyl radical having a (cycloalkyl) alkyl chain selected from the group consisting of (cyclopropyl) methyl, (cyclopropyl) ethyl, (cyclobutyl) methyl; (C 3 -C 10) monoalkenyl and monoalkynylamino having an alkenyl or alkynyl radical selected from the group consisting of allyl, -propinyl, 3-butenyl, 2-butenyl (cis or trans) and 2-pentenyl; (C až-C 10) aralkylamino group selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2- (naphthyl) methyl, 1- (naphthyl) methyl and phenylpropyl; straight or branched symmetrical C 6 -C 14 alkyl radical selected from dibutyl, diisobutyl, disacutyl and dipentylamino; symmetrical dicycloalkylamino of 6 to 14 carbon atoms selected from dicyclopropyl-, dicyclobutyl-, dicyclopentyl- and di (cyclopropyl) methylamino; straight or branched unsymmetrical dialkylamino of 3 to 14 carbon atoms, the total number of carbon atoms /

not more than 14 in both substituents; unsymmetrical dicycloalkylamino of 4 to 14 carbon atoms wherein the total number of carbon atoms in the two substituents is not more than 14; C 2 -C 8 azacycloalkyl and substituted C 2 -C 8 substituted azacycloalkyl selected from the group consisting of 4-methylpiperidine, 4-hydroxypiperidine, 4- (hydroxymethyl) piperidine and 4- (aminomethyl) piperidine, cis-3,4 radicals -dimethylpyrrolidinyl and trans-3,4-dimethylpyrrolidinyl and diastereomers and enantiomers of these azacycloalkyl and substituted azacycloalkyl groups of 2 to 8 carbon atoms; substituted 1-azaoxacycloalkyl group selected from 2-alkylmorpholinyl of 1 to 3 carbon atoms in the alkyl moiety and 3alkylisoxazolidinyl of 1 to 3 carbon atoms in the alkyl moiety; [1, n] -diazacycloalkyl and substituted [1, n] -diazacycloalkyl selected from piperazinyl, 2-alkylpiperazinyl of 1 to 3 carbon atoms in the alkyl moiety, 4-alkylpiperazinyl of 1 to 3 carbon atoms in the alkyl moiety, 2,4-dimethylpiperazinyl and 4-hydroxypiperazinyl and diastereomers or enantiomers of this [1, n] -diazacycloalkyl group and substituted [1, n] -diazacycloalkyl group; 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl selected from thiomorpholinyl and 2-alkylthiomorpholinyl having 1 to 3 carbon atoms in the alkyl moiety; (heterocyclyl) methylamino group selected from 2- or 3-furyl-methylamino, 2- or 3-thienylmethylamino, 2-, 3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino, 2-pyrazinylmethylamino and 2- (imidazolyl) methylamino and substituted (heterocyclyl) methylamino (wherein the substituents are selected from straight or branched (C 1 -C 6) alkyl) 1,1-disubstituted hydrazino selected from 1,130 dimethylhydrazino, N-aminopiperidinyl and 1,1-diethylhydrazino; (C 1 -C 4) alkoxyamino (wherein the alkoxy substituents are selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethylethoxy; arylalkoxyamino of 7 to 11 carbon atoms) selected from benzyloxyamino, 2-phenylethoxyamino, 1-phenylethoxyamino, 2- (naphthyl) methoxyamino,

1- (naphthyl) methoxyamino and phenylpropoxyamino; [beta or gamma-acylamido] (C1-C3) alkylamino group selected from 2- (formamido) ethylamino, 2- (acetamido) ethylamino, 2- (propienylamido) ethylamino,

2- (acetamido) propylamino and 2- (formamido) propylamino and enantiomers of these [beta] - or gamma-acylamidojalkylamino groups having 1 to 3 carbon atoms in the acyl residue; a β- or gamma-alkoxyalkylamino group having 1 to 3 carbon atoms in the alkoxy moiety selected from the group consisting of 2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino,

2-methoxypropylamino, 3-methoxypropylamino,

3-ethoxypropylamino and 3,3-diethoxypropylamino and enantiomers of these β- or gamma-alkoxyalkylamino groups having 1 to 3 carbon atoms in the alkoxy radical; β-, γ- or δ-hydroxyalkylaminoscopyridine having 2 to 4 carbon atoms selected from the group consisting of 3-hydroxypropylamino and 4-hydroxybutylamino; or

R ³ and W together represent a radical of the formula - (CH ₂ ) _n (R 3) N-, wherein n is a number of 3 to 4 and a radical of the formula -CH 2 CH (OH) CH ₂ (r 5) N- up to 3 carbon atoms selected from formyl, acetyl and propionyl, haloacyl having 2 to 3 carbon atoms selected from trifluoroacetyl,

3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl;

R ⁶ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered heterocyclic radicals having an aromatic or saturated ring containing 1 heteroatom of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein Z represents a nitrogen, oxygen, sulfur or selenium atom such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered heterocyclic aromatic ring radicals containing two heteroatoms of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein each of Z and Z ¹ represents a nitrogen, oxygen, sulfur or selenium atom such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5-b] pyridyl or pyridylimidazolyl, - (CH ₂ ) _n COOR ⁸ , wherein n is 0 to 4 and R ⁸ is selected from hydrogen, straight or branched (C 1 -C 3) alkyl group selected from the group consisting of: methyl, ethyl, n-propyl and 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

R ⁷ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C 9) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered heterocyclic radicals having an aromatic or saturated ring containing 1 nitrogen, oxygen, sulfur or selenium heteroatoms to which is optionally fused a benzo or pyrido group of the general formula

wherein Z represents a nitrogen, oxygen, sulfur or selenium atom such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered heterocyclic aromatic ring radicals containing two heteroatoms of nitrogen, oxygen, sulfur or selenium, to which is optionally fused benzo or pyrido, of the general formula

wherein each of Z and Z ¹ represents a nitrogen, oxygen, sulfur or selenium atom such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5-b] pyridyl or pyridylimidazolyl; - (CH ₂ ) _n COOR ⁸ wherein n is 0-4 and R ⁸ is selected from hydrogen; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl;

wherein both R ⁶ and R ⁷ do not simultaneously represent hydrogen atoms; or

R ⁶ and R ⁷ together represent a group of the general formula

- (CH ₂₎ ^β 2 ^(CH 2) 2 "· ^KC * and B is _{(CH2) n} and n = 0-1, -NH, -N-alkyl [wherein the alkyl is straight or branched and containing 1 to 3 carbon atoms], -N-alkoxy of 1 to 4 carbon atoms, oxygen, sulfur or substituted analogues thereof selected from the group consisting of (L or D-proline, ethyl (L or D) prolinate, morpholine, pyrrolidine or piperidine;

and pharmacologically acceptable salts thereof with organic or inorganic acids or metal complexes.

Particular attention of the compounds of the invention is directed to compounds of formula I or II wherein

R is halogen selected from bromine, chlorine and iodine; or a group of the formula -NR 1 R ² , wherein when R is a group of the formula -NR 1 R ² are arl; represents methyl or ethyl,

R ² = methyl or ethyl;

R ³ represents a hydrogen atom;

R ⁴ is hydrogen or C 1 -C 2 alkyl selected from methyl and ethyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

W is a C 7 -C 6 monoalkylamino group selected from the group consisting of heptyl, octyl, nonyl, decyl, undecyl and dodecyl, and the diastereomers and enantiomers of these branched monoalkylamino groups; fluoroalkylamino having 2 carbon atoms selected from the group consisting of

2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl; (C až-C) monocycloalkylamino group selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the diastereomers and enantiomers of the (C až-C mon) monocycloalkylamino group; a mono [(cycloalkyl) alkyl] amino group having 4 to 5 carbon atoms, in a cycloalkyl radical having a (cycloalkyl) alkyl chain selected from the group consisting of (cyclopropyl) methyl and (cyclopropyl) ethyl; monoalkenyl and monoalkynyl having from 3 to 4 carbon atoms in the alkenyl or alkynyl radical having an alkenyl or alkynyl chain selected from the group consisting of allyl and propynyl; a (C 2 -C 7) azacycloalkyl; a substituted (C 2 -C 7) substituted azacycloalkyl group selected from the group consisting of 4-methylpiperidine, 4-hydroxypiperidine and 4- (hydroxymethyl) piperidine; substituted 1-a: a zaoxacycloalkyl group selected from 2-alkylmorpholinyl having 1 to 3 carbon atoms in the alkyl moiety; [1, n] -diazacycloalkyl and a substituted [1, n] -diazacycloalkyl group selected from piperazinyl and 4-alkylpiperazinyl having 1 to 3 carbon atoms in the alkyl moiety;

1-azathiacycloalkyl and substituted 1-azathiacycloalkyl selected from thiomorpholinyl and 2-alkylthiomorpholinyl having 1 to 3 carbon atoms in the alkyl moiety; (heterocyclylmethylamino group selected from 2- or 3-thienylmethylamino, 2-, 3 or 4-pyridylmethylamino; 1,1-disubstituted hydrazino group selected from the group consisting of:

1,1-dimethylhydrazino and N-aminopiperidinyl; [beta or gamma-acylamido] (C1 -C3) alkylamino group selected from 2- (acetamidolethylamino; [beta] - or [gamma] alkoxyalkyloxy group in the alkoxy moiety selected from the group consisting of:

2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino, 2-methoxypropylamino and 3-methoxypropylamino; (C 2 -C 4) β-, gamma- or S-hydroxyalkylamino group selected from 3-hydroxypropylamino and 4-hydroxybutylamino; or

R ³ and W together represent a radical of the formula - (CH ₂ ) _n (R ⁵ ) N- wherein n is 3 and R ⁵ is hydrogen or trifluoroacetyl; .

R ⁶ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; '

R 'represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 137 methylethyl;

wherein both R ⁶ and R ⁷ do not simultaneously represent hydrogen atoms; or

R and R together are - (CH ₂ ) ₂ B (CH ₂ ) ₂ "/ wherein B is (CH ₂ ) _n in which n is 0 to 1, -NH, -N-alkyl [ in which the alkyl is straight or branched and contains 1 to 3 carbon atoms], -N-alkoxy of 1 to 4 carbon atoms, an oxygen atom, a sulfur atom or substituted analogues thereof selected from the group consisting of proline (L or D), ethyl (L or D) prolinate, morpholine, pyrrolidine or piperidine;

and pharmacologically acceptable salts thereof with organic or inorganic acids or metal complexes.

In a further aspect, the invention also provides compounds which are useful as intermediates for the preparation of compounds of formulas I and II, i. compounds of formula III

Y

OH 0

N _{(CH3) 2}

, 0H 1 x ^ nh ₂ OH OH 0 C

(III) where

Y is a group of formula (CH ₂ ) _n X wherein n is 0 to 5 and X is a halogen selected from bromine, chlorine, fluorine and iodine;

R is halogen selected from bromine, chlorine, fluorine and iodine; or R = -NR R ^ ^2, and when R is a group of the formula -NR-R ^2, and R ¹ is H,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or

1,1-dimethylethyl;

when R ¹ represents methyl or ethyl,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

when R ¹ represents n-propyl,

R ² represents n-propyl, 1-methylethyl, n-butyl,

1-methylpropyl or 2-methylpropyl;

when R ¹ represents 1-methylethyl

R ² = n-butyl, 1-methylpropyl, or

2-methylpropyl;

when R ¹ represents n-butyl

R ² represents n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R ¹ represents 1-methylpropyl,

R ² represents 2-methylpropyl; R ³ represents a hydrogen atom; straight or branched (C 4 -C 8) alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-mercaptoalkyl having 1 to 4 carbon atoms selected from mercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl and α-mercaptopropyl; α-hydroxy (C až-Calkyl) alkyl group selected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl and α-hydroxypropyl; carboxyalkyl of 1 to 8 carbon atoms in the alkyl radical; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; substituted (C 6 -C 10) aryl group [in which the substituents are selected from hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 3) trihaloalkyl, nitro, amino, cyano, (C 1 -C 4) alkoxycarbonyl in alkoxy radical, (C 1 -C 3) alkylamino and carboxy]; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; substituted (C7 -C9) aralkyl group [in which the substituents are selected from halogen, C1 -C4 alkyl, nitro, hydroxy, amino, (C1 -C4) mono- or dialkylamino in each of the alkyl radicals, alkoxy C 1-4 alkylsulfonyl;

carbon atoms, cyano and carboxy];

R ⁴ is hydrogen or C 1 -C 6 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

where R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (i.e. the carbon bearing the substituent W) is either DL (i.e. racemate) or L or D (i.e. enantiomer);

and pharmacologically acceptable salts of these compounds with organic and inorganic acids and their metal complexes.

Preferred compounds of formula III are those in which:

Y is a group of formula (CH ₂ ) _n X wherein n is 0 to 5 and X is a halogen selected from bromine, chlorine, fluorine and iodine;

R is halogen selected from bromine, chlorine, fluorine and iodine; or a group of the formula -NR ³ R ² , wherein when R is a group of the formula -NR 1 R ² and R ¹ is a hydrogen atom;

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or

1,1-dimethylethyl;

and when R ¹ represents methyl or ethyl,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

R ³ represents a hydrogen atom; straight or branched (C 4 -C 8) alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-hydroxy (C 1 -C 4) alkyl group selected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl and α-hydroxypropyl; C 1 -C 8 carboxyalkyl; (C až-C 10ry) aryl group selected from phenyl, α-naphthyl or β-naphthyl; substituted (C 6 -C 10) aryl group [in which the substituents are selected from hydroxy, halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl and carboxy]; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; substituted C 7 -C 9 aralkyl [wherein the substituents are selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, cyano and carboxy];

R ⁴ is hydrogen or C 1 -C 4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

and the pharmacologically acceptable salts of these compounds with organic and inorganic acids and their metal complexes.

Particularly preferred compounds of the general formula

III are compounds in which

Y is a group of formula (CH ₂ ) _n X wherein n is 0 to 5 and X is a halogen selected from bromine, chlorine, fluorine and iodine; -

R is halogen selected from bromine, chlorine, fluorine and iodine; or --NR @ 1 --R @ ² , wherein R @ 1 is --NR @ 1 --R @ ² and R @ ¹ is hydrogen,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or

1,1-dimethylethyl;

and when R ¹ represents methyl or ethyl,

R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl; 1-methylpropyl or 2-methylpropyl;

R ³ represents a hydrogen atom; straight or branched (C 4 -C 6) alkyl group selected from butyl, isobutyl, pentyl and hexyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl;

R ⁴ is hydrogen or C 1 -C 3 alkyl selected from methyl, ethyl, propyl and isopropyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

and the pharmacologically acceptable salts of these compounds with organic and inorganic acids and their metal complexes.

Of particular interest is the compounds of formula III in which:

Y is the formula ^{(CH2 X} ^ n ^/ wherein n is 0 to 5, and X is halogen selected from bromo. Chloro, fluoro and iodo;

R is halogen selected from bromine, chlorine and iodine; or a group of the formula -NR 1 R ² , wherein when R is a group of the formula -NR ³ R ² and R ¹ is methyl or ethyl, it is methyl or ethyl;

R ³ represents a hydrogen atom;

R ⁴ is hydrogen or C 1 -C 2 alkyl selected from methyl and ethyl;

wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers);

and the pharmacologically acceptable salts of these compounds with organic and inorganic acids and their metal complexes.

The novel compounds of the present invention can be readily prepared by the procedures illustrated in the following schemes.

The preferred process for the preparation of 7- (substituted) 9 - [(substituted glycyl) amido] -6-demethyl-6-deoxytetracyclines or their mineral acid salts of formula 3 is shown in Scheme I. This procedure employs conventional honey products, e.g. which are readily produced by the reaction of commercially available haloacyl halides

wherein Y, R ³ and R ⁴ are as defined above and Q represents a halogen selected from bromine, chlorine, iodine and fluorine, with 9-amino-7- (substituted) -6-demethyl-6-deoxytetracycline or a salt thereof with with a mineral acid of formula (1). This reaction affords straight or branched 9 - [(haloacyl) amido] -7- (substituted) -6-demethyl-6-deoxytetracyclines or a mineral acid salt of formula (2) in almost quantitative yield. The above-described intermediates, ie, straight or branched 9 [(haloacyl) amido] -7- (substituted) -6-demethyl-6-deoxytetracyclines or their mineral acid salts of formula 2, can be reacted with a whole group of nucleophilic compounds, especially amines, of formula WH, wherein W is as defined above, to give the novel 7- (substituted) -9 - [(substituted glycyl) amido] -6-methyl-6-deoxy-tetracyclines or their mineral acid salts of formula 3 according to the invention.

Scheme I

mineral acid sol

mineral acid sol

In the process shown in Scheme I, 9-amino-7- (substituted) -6-demethyl-6-deoxytetracycline or a salt thereof with a mineral acid of formula I is admixed with:

a) a polar aprotic solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidone (hereinafter abbreviated as DMPU), hexamethylphosphoramide (hereinafter abbreviated to HMPA), dimethylformamide, dimethylacetamide, N- methylpyrrolidone, 1,2-dimethoxyethers or their equivalent;

b) an inert solvent such as acetonitrile, methylene chloride, tetrahydrofuran, chloroform, carbon tetrachloride, 1,2-dichloroethane, carbon tetrachloride, diethyl ether, tert-butyl methyl ether, isopropyl ether, or an equivalent thereof;

c) a base such as sodium carbonate, sodium bicarbonate, sodium acetate, potassium carbonate, potassium bicarbonate, triethylamine, cesium carbonate, lithium carbonate, and their bicarbonate equivalents; and

d) a straight or branched haloacyl halide of the formula

wherein Y, R ³ , R ⁴ and Q are as defined above, such as bromoacetyl bromide, chloroacetyl chloride, 2-bromopropionyl bromide, or equivalents thereof. The halogen represented by the symbol Y and the halide halogen Q in the halogenacyl halide may be the same or different and are selected from the group consisting of bromine, chlorine, iodine and fluorine. Y is a group of formula (CH ₂ ) _n X wherein n is 0 to 5 and X is halogen;

e) maintaining the resulting mixture for 0.5 to 5 hours at a temperature ranging from room temperature to the reflux temperature of the reaction mixture to give 9 - [(haloacyl) amido] -7- (substituted) -6-demethyl-6 a deoxytetracycline of formula 2 or a mineral acid salt thereof.

This intermediate, i. 9 - [(haloacyl) amido] -7- (substituted) -6-demethyl- = 6-deoxytetracycline (2) or a mineral acid salt thereof is mixed with an inert atmosphere of helium, argon or nitrogen with

(a) a nucleophilic compound of formula WH, such as an amine, substituted amine or equivalent thereof, for example methylamine, dimethylamine, ethylamine, n-butylamine, propylamine or n-hexylamine;

b) a polar aprotic solvent such as DMPU, HMPA, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or 1,2-dimethoxyethane; and

c) maintaining the resulting mixture for 0.5 to 2 hours at a temperature ranging from room temperature to the reflux temperature of the reaction mixture to form the desired mixture;

7- (substituted) -9 - [(substituted glycyl) amido] -6-methyl-6-deoxy-tetracycline or a mineral acid salt thereof of formula 3 according to the invention.

Scheme II

In the process of Formula 3, N-alkyl is either a primary amine such as methylamine, ethylamine, benzylamine, methyl glycinate, (L or D) alanine, (L or D) lysine or a substituted analog thereof, or a secondary amine such as morpholine, pyrrolidine, piperidine or substituted schemes thereof with a compound

II in the presence of formaldehyde and an analog, to give the corresponding Mannich base adduct of the general formula IV.

7- (substituted) -9 - ((substituted glycyl) amido] -6-methyl-6-deoxy-tetracyclines can be obtained: in the form of complexes with metals such as aluminum, calcium, iron, magnesium, manganese, or in the form of complex salts, in the form of salts with inorganic or organic acids, or in the form of the corresponding adducts of the Mannich base type, using procedures known to those skilled in the art (Richard).

C. Larock, Comprehensive Organic Transformations, VCH

Publishers 411-415, 1989). It is well known to those skilled in the art that suitable salts are selected on the basis of their physical and chemical stability, flowability, hygroscopicity and solubility. Preferably, 7- (substituted) -9 - [(substituted glycyl) amido] -6-demethyl-6-deoxytetracyclines are obtained in the form of inorganic salts such as salts of hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfuric, or in the form of organic salts such as acetates, benzoates, citrates, salts of cysteine or other amino acids, fumarates, glycolates, maleates, succinates, tartrates, alkylsulfonates or arylsulfonates. Depending on the stoichiometry of the acids used, salt formation occurs on the C (4) -dimethylamino group (using one equivalent of acid) or on both the C (4) -dimethylamino group and the substituent W (using two equivalents of acid). Salts are preferred for oral or parenteral administration.

Some of the compounds shown in Scheme III contain asymmetric centers on the carbon atom bearing W ⁴ . These compounds may therefore exist in at least two stereoisomeric forms. The present invention encompasses both a process for the preparation of a racemic mixture of stereoisomers and a process for the preparation of all stereoisomers of these compounds, whether they are free of, or mixed with, other stereoisomers in any enantiomeric ratio. The absolute configuration of all these compounds can be determined by conventional X-ray crystallography. During the course of the reaction sequences, the stereochemistry at the centers of the tetracycline unit (ie C-4, C-4a, C-5a and C-12a) remains intact.

Biological efficacy

Methods for assessing in vitro antibacterial activity (Table I)

The minimum inhibitory concentration (MIC), ie the lowest antibiotic concentration that inhibits the growth of the test microorganism, is determined by dilution on agar using 0.1 ml Muller-Hinton II agar (Baltimore Biological Laboratories) per well. An inoculum concentration of 1 to 5 x10 ⁵ CFU / ml and an antibiotic concentration range of 32-0.004 μ9 / η1 is used. The MIC is determined after an 18-hour incubation at 35 ° C in a forced air incubator. Tetracycline-sensitive strains and genetically defined strains that are resistant to tetracycline because of their inability to bind bacterial ribosomes (tetM) are used as test microorganisms.

E. coli in vitro protein translation system (Table II)

Based on the methods described in the literature [J. M. Pratt, Coupled Transcription in Prokaryotic Cell-free Systems, Transcription and Translation, and Practical Approach, (B. D. Hames and S. J. Higgins, eds) p. 179-209, IRL Press, Oxford-Washington, 1984] was developed a cell-free in vitro protein translation system using E. coli cell extract of strain MRE 600 (tetracycline-sensitive) and a derivative of strain MRE 600 containing the tetM determinant.

Using the systems described above, the novel tetracycline compounds of this invention are tested for their ability to inhibit protein synthesis in vitro. Each 10 μΐ sample contains S30 extract (complete extract) made from either a tetracycline-sensitive cell strain or an isogenic tetracycline-resistant (tetM) strain, a low molecular weight component required for transcription and translation (ie ATP and GTP), a mixture of 19 amino acids (no methionine), ³⁵ S-labeled methionine, a DNA template (either pBR322 or pUC119), and either dimethylsulfoxide (control) or a new test tetracycline compound (new TC) dissolved in dimethylsulfoxide (DMSO).

The reaction samples were incubated at 37 ° C for 30 minutes.

The countdown starts with the addition of S30 extract, which is the last component to be added. After 30 minutes, 2.5 μΐ of the reaction sample is taken and mixed with 0.5 ml of 1N sodium hydroxide to break down the RNA and tRNA. 2 ml of 25% trichloroacetic acid are added and the mixture is incubated for 15 minutes at room temperature. The trichloroacetic acid precipitate is collected on a Whatman GF / C filter and washed with 10% trichloroacetic acid solution. The filters are dried and the retained radioactivity, which is ³⁵ S-methionine introduced into the polypeptide, is calculated using standard liquid scintillation methods.

The percent inhibition (P.I.) of protein synthesis is calculated according to the following formula:

Radioactivity captured from the sample with new Tc

p.i. = ioo - / - / x 100

Radioactivity captured from contr. samples with DMSO

Evaluation of antibacterial activity in vivo

The therapeutic effects of tetracyclines are determined against acute lethal infections caused by the Smith strain of Staphylococcus aureus. Female CD-1 (Charles River Laboratories) rats weighing 20 ± 2 g are challenged by intraperitoneal injection of sufficient bacteria (suspended in swine mucin) such that the untreated control animals die within 24 to 48 hours. The antibacterial agents contain 0.5 ml of 0.2% aqueous agar and are administered subcutaneously or orally for 30 minutes after infection. When using the oral route of administration, the animals are deprived of food 5 hours before and 2 hours after infection. 5 rats are treated at each dosage level. ~ For the calculation of the middle (median) effective dose (ED _50), the survival ratios of 7 days, from three separate tests.

Test results

The claimed compounds show antibacterial activity against a broad spectrum of tetracycline-sensitive and resistant Gram-positive and Gram-negative bacteria, in particular against E. coli, S. aureus and E. faecalis strains containing tetM and tetD resistance determinants, and against E. coli strains containing determinants, tetB and tetD resistance. As shown in Table I, notable are compounds D, G and K which exhibit excellent in vitro activity against tetracycline-resistant strains containing a tetM resistance determinant (such as S. aureus UBMS 88-5, S. aureus UBMDS 80-1 and 90-2, E. coli UBMS 89-1 and 90-4) and a tetracycline-resistant strain containing tetB resistance determinants (such as E. coli UBMS 88-1 or E. coli TN10C tetB). These compounds also show good activity against E. coli tetA, E. coli tete and E. coli tetD,

- 54 are effective as minocycline against susceptible strains and are more effective than minocycline against various recently isolated bacteria from clinical sources (Table I).

Minocycline and compounds B, C, D, G and H were tested in vitro for the ability to inhibit protein synthesis occurring on either wild-type or tetM protected ribosomes, using a linked transcription and translation system. All compounds tested showed effective inhibition of protein synthesis on wild-type ribosomes. The level of this potency was the same in all cases. Minocycline is not able to inhibit protein synthesis taking place on tetM-protected ribosomes. In contrast, as shown in Table II, compounds B, C, D, G, and H are effective in inhibiting protein synthesis occurring on tetM-protected ribosomes.

Compounds B, C, D, G, and H bind reversibly to their target (ribosome) because bacterial growth is restored when the compound is removed from the culture by washing the organism. The ability of these compounds to inhibit bacterial growth appears to be a direct consequence of their ability to inhibit protein synthesis at the ribosomal level.

The efficacy of compound G against tetracycline susceptible organisms is also demonstrated in vivo in animals infected with S. aureus Smith with _ED50 for intravenous administration is 1-2 mg / kg and ^ED 50, in the case of oral administration is 4-8 mg / kg .

The improved potency of compounds D, G and K is demonstrated by in vitro potency against isogenic strains into which resistance determinants such as tetm and tetB have been cloned (see Table I) and potency to inhibit tetM ribosome protein synthesis (see Table II).

As can be seen from Tables I and II, the compounds of the invention can also be used to prevent and control important veterinary diseases such as diarrhea, urinary tract infections, skin and skin structure infections, ear, nostrils and throat infections, wound infections, mastitis etc.

Identification of compounds in tables

A [7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) -4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10, 10a, 12-octahydro-1, dihydrochloride, 8,10a, 11-tetrahydroxy-10,12-dioxo-2-naphthacenyl] -1- (trifluoroacetyl) -2-pyrrolidinecarboxamide __

B (4S- (4alpha, 12aalpha)) - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 dihydrochloride - [[[(2- (methoxyethyl) amino] acetyl] amino] -1, ll-dioxo-2-naphthacenecarboxamide

C (4S- (4alpha, 12aalpha)) - 9 - [[[(2,2-diethoxyethyl) amino] acetyl] amino] -4,7-bis (dimethylamino) -1,4,4a, 5a, 6a, 11,12a-octahydro-3,10,12,12a-tetrahydroxy-dioxo-2-naphthacenecarboxamide

D [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1 dihydrochloride , ll-dioxo-9 - [[(2- (propenylamino] acetyl] amino] -2-naphthacenecarboxamide dihydrochloride

E (4S- (4alpha, 12aalpha)) - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1 dihydrochloride , ll-dioxo-9 - [[[(2- (pyridinylmethyl) amino] acetyl] amino] -2-naphthacenecarboxamide dihydrochloride

F [7S- (7alpha, 10aalpha)] N - [9- (aminocarbonyl) -4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10, 10a, 12-octahydro-1,8] dihydrochloride, 10 a, ll-tetrahydroxy-10,12dioxo-2-naphthacenyl] -4-tiomorfolínacetamidu

G [7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) -4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10, 10a, 12-octahydro-1, dihydrochloride, 8.10; ll-tetrahydroxy-10,12dioxo-2-naphthacenyl] -4-methyl-l-piperidineacetamide

H HS- (.alpha.) .Alpha.] -4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 dihydrochloride - [[[(3-methoxypropyl) amino] acetyl] amino] -1, ll-dioxo-2-naphthacenecarboxamide

[7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) -4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10, 10a, 12-octahydro-1, dihydrochloride, 8.10; ll-tetrahydroxy-10,12dioxo-2-naphthacenyl] -4-methyl-l-piperazineacetamide

J [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -9 - [[(heptylamino) acetyl] amino-1,4,4a, 5,5a, 6,11,12a-octahydro- 3,10,12,12a-tetrahydroxy1, ll-dioxo-2-naphthacenecarboxamide

K [4S- (4alpha, 12aalpha)] - 9 - [[(cyclopropylmethyl) amino] acetyl] amino] -4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6, dihydrochloride, 11,12a-octahydro-1-3,10,12,12atetrahydroxy, ll-dioxo-2-naphthacenecarboxamide

L (4S- (4alpha, 12aalpha)) - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1 dihydrochloride , ll-dioxo-9 - [[(undecylamine] acetyl] amino] -2-naphthacenecarboxamide dihydrochloride

M [4S- (4alpha, 12aalpha)] - 9 - [(bromoacetyl) amino] -4,7-bis (dimethylamino) -1,4,4a, 5a, 6,11,12a-octahydro-3 dihydrochloride, 10,12,12a-tetrahydroxy1, ll-dioxo-2-naphthacenecarboxamide

N tetracycline minocycline

P monohydrochloride [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11-4,12a-octahydro-3,10,12,12a-tetrahydroxy-9 - [[[(2-hydroxyethyl) amino] acetyl] amino] -1,11-dioxo-2-naphthalecarboxamide

Q [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12atetrahydroxy-9 - [[[ (2-hydroxyethyl) metylaminoJacetyl] amino] ll-dioxo-2-naphthacenecarboxamide

R [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethyl-4-amino-lamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12, 12atetrahydroxy-9 - [[[(4-hydroxybutyl) amino] acetyl] amino] -l, ll-dioxo-2-naphthacenecarboxamide

S [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12atetrahydroxy-1,11-dioxo -9 - [[[2,2,2-trifluoroethyl) amino] acetyl] amino-2-naphthacenecarboxamide

T [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 9 - [[[(2-fluoroethyl) amino] acetyl] amino] 1,4,4a, 5,5a, 6,11,12a octahydro-1-3,10,12,12atetrahydroxy, ll-dioxo-2-naphthacenecarboxamide

U [4S- (4alpha, 12alpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12atetrahydroxy-1,11-dioxo -9 - [[[[2- (1-piperidinyl) ethyl] amino] acetyl] amino] -2-naphthacenecarboxamide

In [4S- (4alpha, 12alpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12atetrahydroxy-9 - [[[ methyl-2-propynylamino] acetyl] amino] -1, ll-dioxo-2-naphthacenecarboxamide

N [4S- (4alpha, 12alpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12atetrahydroxyhydroxy-1,11a -dioxo-9 - [[(1-piperidinylamino) acetyl] amino> -2-naphthacenecarboxamide

X [4S- (4alpha, 12alpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12atetrahydroxy-1,11-dioxo -9 - [[[(phenylmethoxy) amino] acetyl] amino] -2-naphthacenecarboxamide m.p.

- 59 Antibacterial activity of 9 - [(substituted glycyl) amido] 6-demethyl-6-deoxytetracyclines MIC (g / ml)

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Table II

Transcriptional and translational sensitivity to tetracycline compounds in vitro% inhibition

compound concentration wild type S30 TetM B 1.0 mg / ml 98 97 0.25 mg / ml 96 95 0.06 mg / ml .... -92 91 C 1.0 mg / ml 98 96 0.25 mg / ml "95 84 0.06 mg / ml 88 65 D 1.0 mg / ml 99 98 0.25 mg / ml 98 ⁹⁶ 0.06 mg / ml 93 83 G 1.0 mg / ml 99 99 0.25 mg / ml 97 92 0.06 mg / ml 90 83 H 1.0 mg / ml 99 98 0.25 mg / ml 96 94 0.06 mg / ml 88 85 ABOUT 1.0 mg / ml 98 68 0.25 mg / ml 89 43 0.06 mg / ml 78 0

When used as antibacterial agents, the compounds of the invention may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents, and the like. and may be administered orally in such forms as tablets, capsules, dispersible powders, granules or suspensions, containing, for example, about 0.05 to 5% of a suspending agent, syrups containing, for example, about 10 to 50% sugar and elixirs containing, for example about 20 to 50% ethanol and the like. They can also be administered parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to about 5% of a suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, about 25 to about 90% of the active ingredient in combination with a carrier. Often the active ingredient content is about 5 to 60% by weight.

An effective amount of the compound in the range of 2.0 to 100.0 mg / kg body weight should be administered one to five times daily by any conventional route of administration. Suitable routes of administration include, but are not limited to, oral administration, parenteral administration (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion), topical or rectal administration in unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers. , adjuvants and vehicles. Of course, a particular dosage level

The dosage frequency may vary for each particular patient, depending on various factors such as the efficacy of the particular compound used, its metabolic stability and duration of action, age, body weight, general health, sex, diet, time and mode of administration, excretion rate, drug combination, severity of the disease being treated, etc.

The active compounds of the invention may be administered by the oral, intravenous, intramuscular and subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin. Liquid carriers include sterile water, polyethylene glycols, nonionic surfactants, and edible oils such as corn, peanut, and sesame oil, depending on the nature of the active ingredient and the particular mode of administration chosen. Adjuvants commonly used in the manufacture of pharmaceutical preparations include, but are not limited to, flavoring, coloring, preservative and antioxidants such as vitamin E, ascorbic acid, BHT, and BHA.

In terms of ease of manufacture and ease of administration, preferred pharmaceutical formulations are solid formulations, especially tablets, hard capsules, and soft filled liquid capsules. Oral administration of the compounds of the invention is preferred.

The compounds of the invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of the active compounds in the form of the free bases or in the form of pharmacologically acceptable salts can be prepared in water to which a surface-active ingredient such as hydroxypropylcellulose is expediently added. Dispersions can also be made in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, preservatives are added to these preparations to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form chosen must be sterile and must be fluid to the extent that easy syringability exists. The dosage form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycols), suitable mixtures thereof, and vegetable oils.

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the scope of the invention in any way.

Examples of the invention

Example 1

(4S- (4alpha, 12aalpha)) - 9 - [(chloroacetyl) amino] dihydrochloride -

4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacicicarboxamide

To a solution of 0.334 g of 9-amino-4,7-bis (dimethylamino) -6-demethyl-6-deoxytetracycline disulfate, 6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (hereinafter referred to) only DMPU) and 2 ml of room temperature acetonitrile are added 0.318 g of sodium carbonate. The mixture was stirred for 5 minutes and then 0.068 g of chloroacetyl chloride was added. The reaction mixture is stirred for 30 minutes, then filtered and the filtrate is added dropwise to 100 ml of diethyl ether containing 1 ml of 1M hydrochloric acid in diethyl ether. The resulting solid was collected and dried. 0.340 g of the desired intermediate is obtained.

MS (FAB): mlz 549 (M + H).

Example 2

[4S- (4alpha, 12alpha)] -9- [(bromoacetyl) amino] monohydrobromide -

4.7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound was prepared as described in Example 1 using 6.68 g of 9-amino- disulfate.

4.7-bis (dimethylamino) -6-demethyl-6-deoxytetracycline, 50 ml DMPU, 30 ml acetonitrile, 6.68 g sodium carbonate and 0.215 g bromoacetyl bromide. 5.72 g of the desired intermediate are obtained.

MS (FAB): mlz 593 (M + H).

Example 3

[4S- (4alpha, 12alpha)] - 9 - [(bromo-1-oxopropyl) amino] sulfate -

4.7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound was prepared as described in Example 1 using 1.00 g of 9-amino- disulfate.

4.7-bis (dimethylamino) -6-demethyl-6-deoxytetracycline,

1.0 g sodium carbonate and 0.648 g 2-bromopropionyl bromide. 0.981 g of the desired intermediate is obtained.

MS (FAB) m / z 607 (M + H).

Example 4

[4S- (4alpha, 12alpha)) - 9 - ((4-bromo-1-oxobutyl) amino] -4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,1.1,12a dihydrochloride -octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound was prepared as described in Example 1 using 1.34 g of 9-amino- disulfate.

4,7-bis (dimethylamino) -6-demethyl-6-deoxytetracycline, 24 ml DMPU, 8 ml acetonitrile, 1.3 g sodium carbonate and 0.389 g 4-bromobutyryl chloride. 1.45 g of the desired intermediate is obtained.

MS (FAB): mlz 607 (M + H).

Example 5

[7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) - dihydrochloride -

4.7- bis (dimethylamino) -5,5a, 6,7,10,10a, 12-octahydro-1,8,10a, 1-tetrahydroxy-10,12-dioxo-2-naphthacenyl] -1-trifluoroacetyl) -2-pyrrolidinecarboxamide

The title compound was prepared as described in Example 1 using 0.334 g of 9-amino- disulfate.

4.7-bis (dimethylamino) -6-demethyl-6-deoxytetracycline, 10 ml DMPU, 2 ml acetonitrile, 0.34 g sodium carbonate and 7.5 ml 0.1M (S) - (-) - N- (trifluoroacetyl) prolyl. 0.292 g of the expected product is obtained.

MS (FAB): mlz 666 (M + H).

Example 6. I

[4S- (4alpha, 12aalpha)] - 9 - [[[(cyclopropylmethyl) amino] acetyl] amino] -4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6, 11,12a dihydrochloride octahydro-3,10,12,12a-tetrahydroxy-11-dioxo-2-naphthacenecarboxamide

A mixture of 0.20 g of the product of Example 2, 0.50 g of (aminomethyl) cyclopropane and 5 ml of DMPU was stirred at room temperature for 1 hour under argon. Excess amine was removed in vacuo and the residue diluted with a small volume of methanol. The diluted reaction solution was added dropwise to a mixture of diethyl ether and 5 ml of 2-propanol. 1M hydrochloric acid in diethyl ether was added until a solid formed. The resulting solid was collected and dried. 0.175 g of the expected product is obtained.

MS (FAB) m / z 584 (M + H);

Examples 7 to 16

The procedure is essentially as described in detail in Example 6. The starting materials used, reaction conditions, resulting reaction products, and their characteristics are shown in the following table.

At- Title východis- reaction time MS (FAB) EXAMPLE Metallic substance agent reactions m / z product (H) (M + H) no. from Ex.

7 dihydrochloride [4S- (4alpha, 2 2,2-dieto- 12a?)] - 9 - [[[(2,2-diethoxy or xyetyl- ethyl) amino] acetyl] amino] - 1 . amine

4,7-Bis (dimethylamino) -1,4,4a,

646

5,5a, 6,11,12a-octahydro-3,10,

12,12a-Tetrahydroxy-1,11-dioxo2-naphthacene rboxamide dihydrochloride [4S- (4alpha, 12-2aalpha)] - 4,7-bis (dimethylamino) - or

2-methoxyethylamine

588

1,4,4a, 5,5a, 6,11,12a-octahydro-1,10,10,12,12a-tetrahydroxy-9 - [[[2 (methoxyethyl) amino] acetyl] amino] 1,11-dioxo- 2-naphthacenecarboxamide

ΊΟ

EXAMPLE Starting Time MS (FAB) Compound, Reagent m / z Product (h) (M + H)

no. from Ex. 9 [4S- (4alpha, 12-2) dihydrochloride] aalpha] -4,7-bis (dimethylamino) - or 1,4,4a, 5,5a, 6,11,12a-octahydro-1 3,10,12,12a-Tetrahydroxy-1,11-dioxo-9 - [[(2-propenylamino) acetyl] amino] -2-naphthacenecarboxamide aly'Lamín 2 570 10 [4S- (4alpha, 12-2) dihydrochloride] aalpha] -4,7-bis (dimethylamino) - or 1,4,4a, 5,5a, 6,11,12a-octahydro-1,3,10,12,12a-tetrahydroxy-9 [[[(3- methoxypropyl) amino] acetyl] amino] -1, ll-dioxo-2naftacénkarboxamidu 3-methoxypropylamine 2 602 11 dihydrochloride [7S- (7alpha, 10-2) Aalpha)] - N- [9- (Aminocarbonyl) - 4,7-bis (dimethylamino) -5,5a, 6, 6a, 7,10,10a, 12-octahydro-1,8,10a, 11-tetrahydroxy-10,12-dioxo2-naphthacenyl] -4-thiomorpholine acetamide thiomorpholine 3 616 12 dihydrochloride [7S- (7alpha, 10-2) aalpha] - N- [9- (aminocarbonyl) 4,7-bis (dimethylamino), - 5,5a, 6,6a, 7,10,10a, 12-octahydro-1,8,10a, 11-tetrahydroxy- 10,12-dioxo-2-naphthacenyl] -4-methyl-1-piperidineacetamide 4-methylpiperazine € * .ridín 2 612

Pri- Name example

no.

MS (FAB) starting material, reagent m / z product (h) (M + H) from Ex.

[7S- (7alpha, 10-2aalpha)] - N- [9- (aminocarbonyl) 4,7-bis (dimethylamino) -5,5a, 6, dihydrochloride,

6a, 7,10,10a, 12-octahydro-8,

10 a, ll-tetrahydroxy-10,12-dioxo-2-naphthacenyl] -4-methyl-l-piperazineacetamide

4-methyl-0.75 1-piperazine

613 [4S- (4alpha, 12-2aalpha)] - 4,7-bis (dimethylamino-) dihydrochloride

9 - [[heptylamino) acetyl] amino] -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-11dioxo-2-naphthacenecarboxamide

N-heptyl

628 [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro3,10,12,12a-tetrahydroxy-1,11-dioxo- dihydrochloride 9 - [[(undecylamino) acetyl] amino] -2-naphthacenecarboxamide dihydrochloride [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a- octahydro-3,10,12,12a-tetrahydroxy-11dioxo-9 - [[(2-pyridinylmethyl) amino] acetyl] amino] -2-naphthacenecarboxamide dihydrochloride

2 undecylamine 3.5 684 2 2- (amino, methyl) pyridine , · / 1.5 621

Example 17

[4S- (4alpha, 12aalpha)] -4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy 9 - [[ [(2-hydroxyethyl) amino] acetyl] amino] -1,11-dioxo2-naphthalenecarboxamide

To a solution of 0.10 g of the product of Example 7a) in 2 ml

1,3-Dimethyl-2-imidazolidinone was added with 0.70 ml of 2-amino-1-ethanol. The solution was stirred at room temperature for 20 minutes, added to 100 mL diethyl ether and the resulting precipitate collected. 0.055 g of the expected product is obtained. MS (FAB): mlz 574 (M + H).

Examples 18 to 24

The procedure is essentially as described in detail in Example 17. The starting materials used, reaction conditions, resulting reaction products and their characteristics are shown in the following table.

Example

no.

Title Initial MS Reaction Time (FAB) Metal, reagent m / z Product (h) (M + H) from Ex.

[4S- (4alpha, 12aalpha)] - 4,7bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro3,10,12,12a-tetrahydroxy-9 [[[(2- hydroxyethyl) methylamino] acetyl] amino] -1,11dioxo-2-naphthacenecarboxamide

7A 4-Methylamino-1-butanol

0.5

588

EXAMPLE Starting Time MS (FAB) Compound, Reagent m / z Product (h) (M + H)

no. from Ex. 19 [4S- (4alpha, 12alpha)] - 4.7-7A bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro 3,10,12,12a tetrahydroxy-9 [[[(4-hydroxybutyl) amino] - acetyl] amino] -LL-dioxo-2naftacénkarboxamid 4-a: mino- 1-butanol 0.5 602 20 [4S- (4alpha, 12alpha)] - 4.7-7A bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3, 10,12,12a-tetrahydroxy-1,11-dioxo-9 - [[[2-trifluoroethyl) amino] acetyl] -2-naphthacenecarboxamide 2,2,2-trifluórmetylamín 2 612 21 [4S- (4alpha, 12alpha)] - 4.7-7A bis (dimethylamino) -9 - [[[(2-fluoroethyl) amino] acetyl] amino] -1,4,4a, 5,5a, 6,11,12aoktahydro-3,10,12,12a-tetrahydroxy-1, ll- dioxo-2-naphthacenecarboxamide 2-fluoroethylamine 2 . / 576 22 [4S- (4alpha, 12alpha)] - 4.7-7A bis (dimethylamino) -1,4,4a, l- (2-aminoétyljpyro- 2 627

5,5a, 6,11,12a-octahydro-lidin

3,10,12,12a-tetrahydroxy-11dioxo-9 - [[[2- (1-piperidinyl) ethyl] amino] acetyl] amino] -2naftacénkarboxamid

At· Title východis- reaction time MS (FAB) EXAMPLE agent, agent reactions m / z product (H) (M + H) no. from Ex. 23 (4S- (4?, 12a?)] - 4,7- 7A N-methyl- 2 581 bis (dimethylamino) -1,4,4a, propargyl 5,5a, 6,11,12a-octahydro 3,10,12,12a-tetrahydroxy-9 [[[methyl-2-propynylamino] acety1] amino] -1,11-dioxo-2naftacénkarboxamid amine 24 [4S- (4?, 12a?)] - 4,7- 7A 1-aminol- 2 613 bis (dimethylamino) -1,4,4a, * - piperidine 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy 1,11-dioxo-9 - [[(1-piperidinyl amino) acetyl] amino] -2-naphthalenecarboxamide

Example 25 (4S- (4alpha, 12alpha)) - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,

11,12a-octahydro-3,10,12,12a-tetrahydroxy-dioxo-9 [[[(phenylmethoxy) amino] acetyl] amino] -2-naphthacenecarboxamide

To 0.50 g of O-benzylhydroxylamine and 2.5 ml of 1,3-dimethyl-2-imidazolidinone was added 0.80 g of sodium bicarbonate. The resulting mixture was stirred at room temperature for 2 hours, filtered and the filtrate added to 0.10 g of the product of Example 7A. The reaction solution was stirred at room temperature for 2 hours

- 75 room temperature and then added to 100 ml diethyl ether. The resulting precipitate was collected and dried. 0.90 g of the desired product is obtained.

MS (FAB): mlz 636 (M + H).

Claims (12)

PATENT CLAIMS 7- (substituted) -9 - [(substituted glycyl) amido] -6-demethyl-6-deoxytetracyclines of formula I and II (II) wherein: R is halogen selected from bromine, chlorine, fluorine and iodine; or a group of the formula -NR 1 -R ² , wherein when R is a group of the formula -NR 1 R ² and R ¹ is hydrogen, methyl, ethyl, n-propyl, 1-methyl77 ethyl, n-butyl, 1- methylpropyl, 2-methylpropyl or 1,1-dimethylethyl; when R ¹ represents methyl or ethyl, R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl; when R ¹ represents n-propyl, R ² is n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl; when R ³ represents 1-methylethyl R ² = n-butyl, 1-methylpropyl, or 2-methylpropyl; when R ³ represents n-butyl R ² = n-butyl, 1-methylpropyl, or 2-methylpropyl; and when R ¹ represents 1-methylpropyl, R ² = 2-methylpropyl; R ³ represents a hydrogen atom; straight or branched (C 4 -C 8) alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl, and octyl; α-mercapto C 1 -C 4 alkyl group selected from mercaptomethyl, α-mercaptoethyl, ^- a mercapto-1-methylethyl and α-mercaptopropyl; α-hydroxy (C 4-Calkyl) alkyl group selected from hydroxymethyl, α-hydroxyethyl, αhydroxy-1-methylethyl and α-hydroxypropyl; carboxyalkyl of 1 to 8 carbon atoms in the alkyl radical; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; substituted (C 6 -C 10) aryl group [in which the substituents are selected from the group consisting of hydroxy, halogen, (C 1 -C 4) alkoxy, (C 1 -C 3) trihaloalkyl, nitro, amino, cyano, (C 1 -C 4) alkoxycarbonyl in alkoxy radical, C 1 -C 3 alkylamino and carbonyl); (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; substituted (C7 -C9) aralkyl group [in which the substituents are selected from halogen, C1 -C4 alkyl, nitro, hydroxy, amino, (C1 -C4) mono- or dialkylamino in each of the alkyl radicals, alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, cyano and carboxy]; R ⁴ is hydrogen or C 1 -C 6 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl; where R ^{3 has} a meaning other than R ⁴ , it is. stereochemistry at the asymmetric carbon atom (ie, the carbon atom bearing W) either of DL (i.e., the racemate) or L or D (i.e., the individual enantiomers); W is hydroxyamino; (C roz-C 12) monoalkylamino group having a straight or branched alkyl chain selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and diastereomers and enantiomers of these branched monoalkylamino groups; straight or branched (C 1 -C 4) fluoroalkylamino group selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3,3,2,2-pentafluoropropyl, 2,2-difluoropropyl, 4,4,4-trifluorobutyl and 3,3-difluorobutyl; (C až-C) monocycloalkylamino group selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylLcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] hept-2- yl, bicyclo [2.2.2] oct-2-yl, and diastereomers and enantiomers of these C 3 -C 8 monocycloalkylamino groups; C 4 -C 10 mono [(cycloalkyl) alkyl] amino in a cycloalkyl radical with a (cycloalkyl) alkyl chain selected from (cyclopropyl) methyl, (cyclopropyl) ethyl, (cyclobutyl) methyl, (trans 2-methylcyclopropyl) methyl and ( cis-2-methyl-cyclobutyl) methyl; (C 3 -C 10) monoalkenyl and monoalkynylamino of an alkenyl or alkynyl radical having an alkenyl or alkynyl chain selected from allyl, 3-butenyl, 2-butenyl (cis or trans), 2-pentenyl, propynyl, 4-oct.enyl . 2,3-dimethyl-2-butenyl, 3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl; (C6 -C10) monoarylamino having an aryl radical selected from phenyl and naphthyl; (C až-C 10) aralkylamino group selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2- (naphthyl) methyl, 1- (naphthyl) methyl and phenylpropyl; (C 6 -C 10) monoarylamino of which the aryl radical is substituted by substituents selected from C 1 -C 5 acyl, C 1 -C 5 acylamino, C 1 -C 4 alkyl, C 1 -C 8 monoalkylamino or C 1 -C 8 dialkylamino carbon in each of the alkyl radicals, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl, amino, carboxy, cyano, halogen, phyroxy, nitro and trihaloalkyl of 1 to 4 carbon atoms; 3 carbon atoms; straight or branched symmetrical C 6 -C 14 alkyl radical selected from dibutyl-, diisobutyl-, disac-butyl-, dipentyl-, diisopentyl-, disac. pentyl-, dihexyl-, diisohexyl- and disa-hexylamino; symmetrical dicycloalkylamino of 6 to 14 carbon atoms selected from dicyclopropyl, dicyclobutyl, dicyclopentyl, di (cyclopropyl) methyl, dicyclohexyl and dicycloheptylamino; straight or branched unsymmetrical dialkylamino of 3 to 14 carbon atoms, the total number of carbon atoms in both substituents not exceeding 14; unsymmetrical dicycloalkylamino of 4 to 14 carbon atoms wherein the total number of carbon atoms in the two substituents is not more than 14; C 2 -C 8 azacyCloalkyl and substituted C 2 -C 8 substituted azacycloalkyl selected from the group consisting of 4-methylpiperidine, 4-hydroxypiperidine, 4- (hydroxymethyl) piperidine and 4- (aminomethyl) piperidine, cis-3,4- dimethylpyrrolidinyl, trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo [2.1.1] hex-2-yl, 5-azabicyclo [2.1.1] hex-5-yl, 2-azabicyclo [2.2.1] hept-2-yl, 7-azabicyclo [2.2.1] hept-7-yl, and 2-azabicyclo [2.2.2] oct-2-yl and diastereomers and enantiomers of these azacycloalkyl and substituted azacycloalkyl groups of 2 to 8 carbon atoms; substituted 1-azaoxacycloalkyl group selected from 2-alkylmorpholinyl having 1 to 3 carbon atoms in the alkyl moiety, 3-alkyl isoxazolidinyl having 1 to 3 carbon atoms in the alkyl moiety, tetrahydrooxazinyl and 3,4-dihydrooxazinyl; [1, n] -diazacycloalkyl and a substituted [1, n] diazacycloalkyl group selected from piperazinyl, 2-alkylpiperazinyl of 1 to 3 carbon atoms in the alkyl moiety, 4-alkylpiperazinyl of 1 to 3 carbon atoms in the alkyl moiety, 2,4-dimethylpiperazinyl, 4-alkoxypiperazinyl of 1 to 4 carbon atoms in the alkoxy moiety, 4-aryloxypiperazinyl of 6 to 10 carbon atoms in the aryl moiety, 4-hydroxypiperazinyl, 2,5-diazabicyclo [2.2.1] hept-2- yl, 2,5-diaza-5-methylbicyclo [2.2.1] hept-2-yl, 2,3-diaza-3-methylbicyclo [2.2.2] oct-2-yl, 2,5-diaza -5,7-dimethylbicyclo- [2.2.2] oct-2-yl and diastereomers or enantiomers of this [1, n] -diazacycloalkyl and substituted [1, n] -diazacycloalkyl; 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl selected from thiomorpholinyl, 2-alkylthiomorpholinyl having 1 to 3 carbon atoms in the alkyl moiety and 3-cycloalkylthiomorpholinyl having 3 to 6 carbon atoms in the cycloalkyl moiety; N-azolyl and substituted N-azolyl selected from 1-imidazolyl, 2-alkyl-1-imidazolyl of 1 to 3 carbon atoms in the alkyl moiety, 3-alkyl-1-imidazolyl of 1 to 3 carbon atoms in the alkyl moiety, 1-pyrrolyl, 2-alkyl-1-pyrrolyl of 1 to 3 carbon atoms in the alkyl moiety, 3-alkyl-1-pyrrolyl of 1 to 3 carbon atoms in the alkyl moiety, 1-pyrazolyl, 3-alkyl-1-pyrazolyl of 1 to 3 3 carbon atoms in the alkyl moiety, indolyl, 1- (1,2,3-triazolyl), 4-alkyl-1- (1,2,3-triazolyl) with 1 to 3 carbon atoms in the alkyl moiety, 5-alkyl-1- (1,2,3-triazolyl) ) having 1 to 3 carbon atoms in the alkyl moiety, 4- (1,2,4-triazolyl), 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl; (heterocyclyl) amino wherein the heterocyclic radical is selected from 2- or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 5-pyridazinyl, 2-pyrazinyl, 2-imidazolyl, benzimidazolyl and benzothiazolyl and substituted (heterocyclyl) amino (wherein the substituents are selected from the group consisting of straight and branched (C 1 -C 6) alkyl groups (heterocyclyl) methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3 or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino, (benzimidazolyl) methylamino and (benzothiazolyl) methylamino and substituted (heterocyclyl); (methylamino) (wherein the substituents are selected from the group consisting of straight and branched (C 1 -C 6) alkyl; (C 2 -C 4) carboxyalkylamino group selected from aminoacetic acid, α-aminopropionic acid, β-aminopropionic acid, α -aminobutyric acid, β-aminobutyric acid and enantiomers of these C 2 -C 4 carboxyalkylamino groups a 1,1-disubstituted hydrazino group selected from 1,183 dimethylhydrazino, N-aminopiperidinyl, 1,1-diethylhydrazino and N-aminopyrrolidinyl; (C 1 -C 4) alkoxy amino group (wherein the alkoxy substituents are selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethylethoxy; C 3 -C 8 cycloalkoxyamino selected from the group consisting of cyclopropoxy, trans-1,2-dimethylcyclopropoxy, cis-1,2-dimethylcyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cycloocthoxy, bicyclo [2.2.1] hept-2-yloxy, bicyclo [2.2.2] oct-2-yloxy and diastereomers and enantiomers of these C 3 -C 8 cycloalkoxyamino C 6 -C 10 aryloxyamino selected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino; . 1-phenylethoxyamino, 2- (naphthyl) methoxyamino, 1- (naphthyl) methoxyamino and phenylpropoxyamino; a (p- or gamma-acylamido) alkylamino group having 1 to 3 carbon atoms in the acyl radical selected from the group consisting of 2- (formamido) ethylamino, 2- (acetamido) ethylamino, 2- (propionylamido) ethylamino, 2- (acetamido) propylamino, 2- (formamido) propylamino, and the enantiomers of these [beta- or gamma-acylamido] alkylamino-C 1 -C 3 alkylamino acids a β- or gamma-alkoxyalkylamino group having 1 to 3 carbon atoms in the alkoxy moiety selected from 2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino, 2-methoxypropylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 3 , 3-diethoxypropylamino and enantiomers of these β- or γ-alkoxyalkylamino groups having 1 to 3 carbon atoms in the alkoxy radical; β-, gamma- or δ-hydroxyalkylamino group having 2 to 4 carbon atoms selected from 2-hydroxyethylamino, 2-hydroxypropylamino, 3- hydroxypropylamino and 4hydroxybutylamino, or R ³ and W together represent a radical of the formula - (CH 2) n (R ⁵ ) N- wherein n is a number of 3 to 4 and the radical of the formula -CH 2 CH (OH) CH ₂ (R ⁵ ) N- wherein R ⁵ represents a hydrogen atom or (C až-C) acyl group selected from formyl, acetyl and propionyl, haloacyl group of 2 to 3 carbon atoms selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl; R ⁶ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered aromatic or saturated ring heterocyclic radicals containing 1 nitrogen, oxygen, sulfur or selenium heteroatoms, to which is optionally fused benzo or pyrido, of the general formula wherein Z is nitrogen, oxygen, sulfur or selenium such as is pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered aromatic ring heterocyclic radicals containing two nitrogen, oxygen, sulfur, heteroatoms selenium, optionally having a benzo or pyrido fused, of the formula wherein each of Z and Z ¹ is N, O, S or Se ,, such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo [4,5-b] pyridine idyl or pyridylimidazolyl, a five-membered saturated ring heterocyclic radical containing one or two heteroatoms of nitrogen, oxygen, sulfur or selenium to which is attached an oxygen heteroatom, generally [wherein A represents a hydrogen atom; straight or branched (C 1 -C 4) alkyl; (C 6-Cry) aryl; substituted (C 6-Cryry) aryl (in which the substituents are selected from halogen, (C až-C alko) alkoxy, (C až-C tr) trihaloalkyl, nitro, amino, cyano, (C alko-C alko) alkoxycarbonyl) (C 1 -C 3 alkylamino and carboxy); (C 7 -C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl] such as gamma-butyrolactam, gamma-butyrolactone, imidazolidinone or N-aminoimidazolidinone, 6-membered heterocyclic radicals containing 1 to 3 aromatic ring atoms nitrogen, such as pyridyl, pyridazinyl, pyrazinyl, symtriazinyl, unsymmetriazinyl, pyrimidinyl or alkylthiopyridazinyl having 1 to 3 carbon atoms in the alkyl moiety and six-membered saturated ring heterocyclic radicals containing one or two heteroatoms of nitrogen, oxygen, sulfur or selenium, to which is attached an oxygen heteroatom such as 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2 -dioxo-1-piperazinyl, 2-dioxomorpholinyl or 2-dioxothiomorpholinyl; - (CH ₂ ) _n COOR ⁸ wherein n is 0-4 and R ⁸ is selected from hydrogen; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; (C až-C) aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclic group selected from the group consisting of five-membered aromatic or saturated ring heterocyclic radicals containing 1 nitrogen, oxygen, sulfur or selenium heteroatoms, to which is optionally fused benzo or pyrido, of the general formula wherein Z is nitrogen, oxygen, sulfur or selenium such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, five-membered aromatic ring heterocyclic radicals containing two heteroatoms of nitrogen, selenium, sulfur or wherein each of Z and Z ¹ is N, O, S, or selenium such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3- alkyl-3H-imidazo [4,5-b] pyridine 1 or pyridylimidazolyl, a five-membered saturated ring heterocyclic radical containing one or two heteroatoms of nitrogen, oxygen, sulfur or selenium to which an oxygen heteroatom is attached, of the general formula [wherein A is hydrogen; straight or branched (C 1 -C 4) alkyl; (C 6-Cry) aryl; substituted (C 6-Cryry) aryl group (wherein the substituents are selected from the group consisting of halogen, (C až-C alko) alkoxy, (Cih-C tr) trihaloalkyl, nitro, amino, cyano, (C alko-C alko) alkoxycarbonyl, (C až-C časti) alkoxy) (C 1 -C 3 alkylamino and carboxy); (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2- (phenylethyl and phenylpropyl) such as gamma-butyrolactam, gamma-butyrolactone, imidazolidinone or N-aminoimidazolidinone, 6-membered heterocyclic radicals containing aromatic 1 to 3 nitrogen heteroatoms such as pyridyl, pyridazinyl, pyrazinyl, symtriazinyl, unsymmetriazinyl, pyrimidinyl or alkylthiopyridazinyl having 1 to 3 carbon atoms in the alkyl moiety and six-membered saturated ring heterocyclic radicals containing one or two nitrogen, oxygen, sulfur or selenium to which is attached an oxygen heteroatom such as 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl, 4 -cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or 2-dioxothiomorpholinyl; - (CH ₂ ) _n COOR ⁸ wherein n is 0-4 and R ⁸ is selected from hydrogen; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; wherein both R ⁶ and R ⁷ do not simultaneously represent hydrogen atoms; or R ⁶ and R ⁷ together represent a group of the formula - (CH 2) 2 ^B ( ^c H 2) 2 - wherein B represents a (CH ₂ ) _n group in which n is 0 to 1, -NH, -N-alkyl [in which the alkyl is straight or branched and contains 1 to 3 carbon atoms], -N-alkoxy of 1 to 4 carbon atoms, an oxygen atom, a sulfur atom or substituted analogues thereof selected from the group consisting of proline (L or D), ethyl (L or D) prolinate, morpholine, pyrrolidine or piperidine; and pharmacologically acceptable salts thereof with organic or inorganic acids or metal complexes. Compounds according to claim 1, wherein 90 R is halogen selected from the group consisting of bromine, chlorine and iodine; or a group of the formula -NR 1 R ² , wherein when R is a group of the formula -NR ¹ R ² and R ¹ is methyl or ethyl, R ² = methyl or ethyl; R ³ represents a hydrogen atom; R ⁴ is hydrogen or C 1 -C 2 alkyl selected from methyl and ethyl; wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (i.e. the carbon bearing the substituent W) is either DL (i.e. racemate) or L or D (i.e. enantiomer); W is a 7 to 6 monoalkylamino group C 12 and straight or branched chain alkyl selected from heptyl, octyl, nonyl, decyl, undecyl and dodecyl and the diastereomers and enantiomers of these branched monoalkylamino groups; fluoroalkylamino having 2 carbon atoms selected from the group consisting of 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl; (C až-C) monocycloalkylamino group selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the diastereomers and enantiomers of the (C 3-C mon) monocycloalkylamino group; mono [(cycloalkyl) alkyl] amino having 4 91 to 5 carbon atoms in the cycloalkyl radical with a (cycloalkyl) alkyl chain selected from the group consisting of (cyclopropyl) methyl and (cyclopropyl) ethyl; monoalkenyl and monoalkynyl having from 3 to 4 carbon atoms in the alkenyl or alkynyl radical having an alkenyl or alkynyl chain selected from the group consisting of allyl and propynyl; C 2 -C 7 azacycloalkyl and substituted C 2 -C 7 substituted azacycloalkyl selected from the group consisting of 4-methylpiperidine, 4-hydroxypiperidine, and 4- (hydroxymethyl) piperidine; substituted 1-azaoxacycloalkyl group selected from 2-alkylmorpholinyl having 1 to 3 carbon atoms in the alkyl moiety; [1, n] -diazacycloalkyl and substituted [1, n] -diazacycloalkyl selected from piperazinyl and 4-alkylpiperazinyl of 1 to 3 carbon atoms in the alkyl moiety; 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl selected from thiomorpholinyl and 2-alkylthiomorpholinyl having 1 to 3 carbon atoms in the alkyl moiety; (heterocyclyl) methylamino group selected from 2- or 3-thienylmethylamino, 2-, 3 or 4-pyridylmethylamino; 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino and N-aminopiperidinyl; [beta or gamma-acylamido] alkylamino (C 3-C 3) acyl radical selected from 2- (acetamido) ethylamino; β- or gamma-alkoxyalkylamino (C až-C 3) alkoxy selected from C súboru-C 2- alko; 2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino, 2-methoxypropylamino and 3-methoxypropylamino; (C 2 -C 4) β-, gamma- or δ-hydroxyalkyl- amino group selected from 3-hydroxypropylamino and 4-hydroxybutylamino; or R ³ and W together represent a radical of the formula - (CH ₂ ) _n (R ⁵ ) N-, wherein n is 3 and represents a hydrogen atom or trifluoroacetyl; R ⁶ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; R ⁷ represents a hydrogen atom; straight or branched (C 1 -C 3) alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; wherein both R ⁶ and R ⁷ do not simultaneously represent hydrogen atoms; or R ⁶ and R ^{7 taken} together are - (CH ₂ ) ₂ B (CH ₂ ) ₂ -, wherein B is (CH ₂ ) _n in which n is 0 to 1, -NH, -N- alkyl [in which the alkyl is straight or branched and contains 1 to 3 carbon atoms], -N-alkoxy of 1 to 4 carbon atoms, an oxygen atom, a sulfur atom or substituted analogues thereof selected from the group consisting of (L or D) proline, ethyl (L or D) prolinate, morpholine, pyrrolidine or piperidine; and pharmacologically acceptable salts thereof with organic or inorganic acids or metal complexes. Compounds of formula III (III) wherein Y is a group of the formula (C 1 -JpX) wherein n is 0 to 5 and X is a halogen selected from bromine, chlorine, fluorine and iodine; R is halogen selected from bromine, chlorine, fluorine and iodine; or a group of the formula -NR 1 -R ² , wherein when R is a group of the formula -NR 1 -R ² ar 1; represents a hydrogen atom, R ² is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl; when R ¹ represents methyl or ethyl, R ² = methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl; t when R ¹ represents n-propyl, R ² represents n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl; when R ¹ represents 1-methylethyl R ² represents n-butyl, 1-methylpropyl or 2-methylpropyl; when R ¹ represents n-butyl R ² represents n-butyl, 1-methylpropyl or 2-methylpropyl; and when R ¹ represents 1-methylpropyl, R ² represents 2-methylpropyl; R ³ represents a hydrogen atom; straight or branched (C 4 -C 8) alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl; α-mercaptoalkyl having 1 to 4 carbon atoms selected from mercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl and α-mercaptopropyl; α-hydroxyalkyl, C 1 -C 4 group selected from hydroxymethyl, α-hydroxyethyl, ahydroxy-1-methylethyl and α-hydroxypropyl; carboxyalkyl of 1 to 8 carbon atoms in the alkyl radical; (C až-Cryry) aryl group selected from phenyl, α-naphthyl and β-naphthyl; substituted (C 6 -C 10) aryl group [in which the substituents are selected from the group consisting of hydroxy, halogen, alkoxy of (C 1 -C 4), (C 1 -C 3) trihaloalkyl, nitro, amino, cyano, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 3) alkylamino and carboxy]; (C až-C 9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; substituted (C7 -C9) aralkyl group [in which the substituents are selected from halogen, C1 -C4 alkyl, nitro, hydroxy, amino, (C1 -C4) mono- or dialkylamino in each of the alkyl radicals, alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, cyano and carboxy]; R ⁴ is hydrogen or C 1 -C 6 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl; wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers); and the pharmacologically acceptable salts of these compounds with organic, β and inorganic acids and their metal complexes. Compounds according to claim 3, in which Y is a group of formula (CH ₂ ) _n X wherein n is 0 to 5 and X is a halogen selected from bromine, chlorine, fluorine and iodine; R is halogen selected from bromine, chlorine and iodine; or a group of the formula -NR ¹ R ² , wherein when R is a group of the formula -NR 1 R ² and R ¹ is methyl or ethyl, R ² = methyl or ethyl; R ³ represents a hydrogen atom; R ⁴ is hydrogen or C 1 -C 2 alkyl selected from methyl and ethyl; wherein when R ^{3 is} other than R ⁴ , the stereochemistry at the asymmetric carbon atom (ie, the carbon bearing the substituent W) is either DL (ie, the racemate) or L or D (ie, the individual enantiomers); and the pharmacologically acceptable salts of these compounds with organic and inorganic acids and their metal complexes. Compounds according to claim 1 or 2, wherein the salts and complexes include salts and complexes with hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric, sulfuric, acetic, benzoic and citric acid, cysteine, fumaric, glycolic, maleic, succinic, tartaric acid. , alkylsulfone and arylsulfone, aluminum, calcium, iron, magnesium or manganese. Compounds according to claim 1, selected from the group consisting of [4S- (4alpha, 12alpha)] - 9 - [[(cyclopropylmethyl) amino] acetyl] amino] -4,7-bis (dimethylamino) -1,4 dihydrochloride, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-11dioxo-2-naphthacenecarboxamide dihydrochloride; [4S- (4alpha, 12aalpha)) - 9 - ([[(2,2'-diethoxyethyl) amino] acetyl] amino] -4,7-bis (dimethylamino) -1,4,4a, 5a, 6a dihydrochloride , l l, 12a-octahydro-3,10,12,12a-tetrahydroxy-11dioxo-2-naphthacenecarboxamide dihydrochloride; (4S- (4alpha, 12aalpha)) - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 [[[dihydrochloride] [(2- (methoxyethyl) amino] acetyl] amino] -1,11-dioxo-2-naphthacenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxyl, 11-dioxo dihydrochloride -9 - [[(2- (propenylamino] acetyl] amino] -2-naphthacenecarboxamide dihydrochloride; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 [[ [(3-methoxypropyl) amino] acetyl] amino] -1,11-dioxo-2-naphthacenecarboxamide; [7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) - dihydrochloride - 4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10,10a, 12-oktahydro1,8,10a, ll-tetrahydroxy-10,12-dioxo-2- naphthacenyl] -4tiomorfolínacetamidu; [7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) - dihydrochloride - 4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10,10a, 12-oktahydro1,8,10a, ll-tetrahydroxy-10,12-dioxo-2-naphthacenyl] -4-methyl-1- piperidineacetamide; [7S- (7alpha, 10aalpha)] - N- [9- (aminocarbonyl) - dihydrochloride - 4,7-bis (dimethylamino) -5,5a, 6,6a, 7,10,10a, 12-octahydro- 1,8,10a, 11-tetrahydroxy-10,12-dioxo-2-naphthacenyl] -4-methyl- 1-piperazine acetamide; [4S- (4alpha, 12aalpha)] -4,7-bis (dimethylamino) 9 - [[(heptylamino) acetyl] amino-1,4,4a, 5,5a, 6,11,12a-octahydro3,10 dihydrochloride, 12,12a-tetrahydroxy-dioxo-2-naphthacenecarboxamide dihydrochloride; (4S- (4alpha, 12alpha)) - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy- dihydrochloride 1.11-dioxo-9 - [[(undecylamino] acetyl] amino] -2-naphthacenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy- 1.11-Dioxo-9 - [[[(2- (pyridinylmethyl) amino] acetyl] amido] - 2- on phthacenecarboxamide; [4S- (4alpha, 12aalpha)] -4,7-bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 monohydrochloride [[ [(2-hydroxyethyl) amino] acetyl] amino] -1,11-dioxo-2-naphthacenecarboxamide; (4S- (4?, 12a?)] - 4,7-Bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 - [[[(2-hydroxyethyl) methylamino] acetyl] amino] -1,11-dioxo-2-naphthalenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9- [ [[(4 (hydroxybutyl) amino] acetyl] amino] -1,11-dioxo-2-naphtacenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9 - [[[2,2,2-trifluoroethyl) amino] acetyl] amino-2-naphthacenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -9 - [[[(2fluoroethyl) amino] acetyl] amino] -1,4,4a, 5,5a, 6,11,12aoctahydro -3,10,12,12a-tetrahydroxy-dioxo-2naftacénkarboxamid; 4S- (4?, 12a?)] - 4,7-Bis (dimethylamino) 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo9 - ([[[2- (1-piperidinyl) ethyl] amino] acetyl] amino] -2-naphthacenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5, 5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9 [[[methyl-2-propynylamino] acetyl] amino] -1,11-dioxo-2-naphthacenecarboxamide; [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-hydroxy-1,1-dioxo-9 - [[(1-piperidinylamino) acetyl] amino] -2-naphthacenecarboxamide; and [4S- (4alpha, 12aalpha)] - 4,7-bis (dimethylamino) -1,4,4a, 5, 5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9 - [[[(phenylmethoxy) amino] acetyl] amino] -2-naphthacenecarboxamide. 7. A process for the preparation of compounds of the formula I or their salts with organic or inorganic acids or their complexes with metals of the formula I to: 100 (I) wherein the general symbols are as defined in claim 1, according to claim 1, characterized in that 9 [(haloacyl) amido] -7- (substituted) -6-demethyl-6-deoxytetracycline or an inorganic salt thereof or an organic acid or metal complex of the general formula III (III) wherein the general symbols are as defined in claim 3, reacted with a nucleophilic compound of the formula WH, wherein W is as defined in claim 1, in a polar aprotic solvent and under an inert atmosphere. A process for the preparation of compounds of the formula III or their salts with organic or inorganic acids or their complexes with metals. (III) 101 wherein each symbol is as defined in claim 3, wherein 9 amino-7- (substituted) -6-demethyl-6-deoxytetracycline or an organic or inorganic acid salt thereof or a complex thereof a metal of formula 1 wherein R is as defined above, is reacted with a straight chain or branched halacyl halide of formula Q wherein Y, R ³ and R ⁴ are as defined in claim 1 and Q is halogen selected from bromine, chlorine, iodine and fluorine, in an inert solvent and a polar aprotic solvent, in the presence of a base. Compounds according to claim 1, for preventing, treating or controlling bacterial infections in warm-blooded animals. 102 10. A pharmaceutical formulation comprising a pharmacologically effective amount of a compound according to claim 1 in association with a pharmaceutically acceptable carrier. 11. A veterinary preparation comprising a pharmacologically effective amount of a compound according to claim 1 in association with a pharmaceutically acceptable carrier. Compounds according to claim 1 for the prevention, treatment or suppression of bacterial infections in warm-blooded animals caused by bacteria showing TetM and TetK resistant determinants.